CN110590609A - Fluorine-containing sulfonyl compound, intermediate, preparation method and application thereof - Google Patents

Fluorine-containing sulfonyl compound, intermediate, preparation method and application thereof Download PDF

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CN110590609A
CN110590609A CN201810609858.6A CN201810609858A CN110590609A CN 110590609 A CN110590609 A CN 110590609A CN 201810609858 A CN201810609858 A CN 201810609858A CN 110590609 A CN110590609 A CN 110590609A
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compound
nmr
fluorosulfonyl
reaction
cdcl
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董佳家
杨倩
郭太杰
詹雄杰
孟根屹
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Shanghai Institute of Organic Chemistry of CAS
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Shanghai Institute of Organic Chemistry of CAS
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Priority to CN201810609858.6A priority Critical patent/CN110590609A/en
Priority to US16/766,193 priority patent/US11091442B2/en
Priority to EP18880337.3A priority patent/EP3715342A4/en
Priority to JP2020528276A priority patent/JP7339677B2/en
Priority to PCT/CN2018/116922 priority patent/WO2019101132A1/en
Publication of CN110590609A publication Critical patent/CN110590609A/en
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Abstract

The invention discloses a fluorine-containing sulfonyl compound, an intermediate, a preparation method and application thereof. The invention discloses a fluorine-containing sulfonyl compound, which comprises a cation and an anion, wherein the cation isAs shown in equation 1. The fluorine-containing sulfonyl compound can react with a substrate to efficiently synthesize a fluorine sulfonylation product, has low toxicity, simple preparation and convenient use, and is in a solid stable state at normal temperature; in addition, the compound has extremely wide substrate adaptability, can comprise phenolic compounds and amine compounds, is the only solid form reagent which can realize the chemical transformation at present, and has important academic and application values.

Description

Fluorine-containing sulfonyl compound, intermediate, preparation method and application thereof
Technical Field
The invention relates to a fluorine-containing sulfonyl compound, an intermediate, a preparation method and application thereof.
Background
The main family high-valence fluoride has high chemical stability, but the activation thereof under specific conditions can realize the transformation and linkage of extremely efficient chemical bonds. The combination of the peculiar stability and reactivity determines that the compounds have unique potential application in organic synthetic chemistry, material chemistry, chemical biology and medicinal chemistry. The success of the hexavalent sulfur fluorine Exchange reaction sulfurfur (vi) Fluoride Exchange (SuFEx) is based on the specific reactivity of the hexavalent sulfur fluorine bond. Since the hexavalent sulfur-fluorine exchange reaction is firstly proposed and successfully realized in 2014 (Angew. chem. int. Ed.2014,9430) by the professor K.Barry Sharpless and the professor Jiajia Dong, the reaction has attracted extensive attention in the aspects of organic synthetic chemistry, material chemistry, pharmaceutical chemistry, chemical biology, particularly protein molecule selective marking and modification and the like, and has shown a good application prospect, which is called new generation click chemistry and triggers a new hot spot of the current fluorine chemistry research. Among a series of widely available hexavalent sulfur fluorine functional groups, the fluorosulfonyl functional group is most widely used. Depending on the kind of atoms to which the sulfur atom is directly linked, such functional groups can be further subdivided into: sulfonyl fluoride group (C-SO)2F, sulfo Fluoride, the sulfur atom being directly bonded to the carbon atom in the molecule), fluorosulfonate group (O-SO)2F, fluorosulfonate, the sulfur atom being directly linked to the oxygen atom in the molecule); and sulphamoyl fluoride (N-SO)2F, sulfoamyl Fluoride, the sulfur atom being directly linked to the nitrogen atom in the molecule). The systematic synthesis of this series of functional groups is systematically discussed in the article of hexavalent sulfur fluorine exchange (angelw.chem.int.ed.2014, 9430).
In the above literature reports, Dong and Sharpless used a compound called sulfuryl fluoride (SO)2F2A large-scale industrially used fumigant, Sulfuryl Fluoride, trade name: vikane) to achieve direct conversion of phenolic compounds (ArOH, Ar ═ aryl) to fluorosulfonate groups (ArO-SO)2F) And secondary amine compound (R)xRyNH) directly into sulphamoyl fluoride (R)xRyN-SO2F, sulfoamyl Fluoride). These two types of functional groups are currently the best synthetic methods described in the literature. Although sulfuryl fluoride can be synthesized very efficiently into-OSO2F，-NSO2F, the synthesis of the series of compounds in a laboratory by using sulfuryl fluoride also has extremely obvious defects: the compound is a fumigating gas with certain toxicity, and the gas is difficult to obtain in many countries in the world including areas with developed chemical industry, such as Europe, America, Japan, and many areas with underdeveloped chemical industry due to control; furthermore, most laboratories needing to use the sulfuryl fluoride-based compounds are chemical biology laboratories and material chemistry laboratories, and the laboratories of non-professional synthetic chemistry have difficulty in using the compounds.
Disclosure of Invention
The invention aims to overcome the defects that the existing fluorosulfonyl group reagent in the field is high in toxicity, cannot be popularized and applied, is difficult to prepare and the like, and further provides a fluorosulfonyl group-containing compound, an intermediate, a preparation method and application thereof. The fluorine-containing sulfonyl compound can efficiently synthesize a fluorine sulfonyl product, has small toxicity, simple preparation and convenient use, is in a stable solid state at normal temperature, has extremely wide substrate adaptability, is the only solid-state reagent which can realize the chemical transformation at present, and has better academic and application values.
The present invention solves the above problems by the following means.
The invention provides a fluorine-containing sulfonyl compound, which comprises a cation and an anion, wherein the cation is shown as a formula 1:
wherein R is1、R2、R3And R4Each independently is hydrogen or C1-6Alkyl, or R3And R4And the carbon atoms in between form unsaturated C5-C8A cyclic hydrocarbon group.
In a certain embodiment, when R3And R4And the carbon atoms in between form unsaturated C5-C8When it is a cyclic hydrocarbon group, said "unsaturated C" is5-C8Cycloalkyl "is a benzene ring.
In one embodiment, the fluorosulfonyl compound is comprised of the cation and an anion.
In a certain embodiment, when R1Is C1-6When alkyl, said C1-6Alkyl is C1-4Alkyl (for example methyl, ethyl, isopropyl or butyl, and also for example methyl or butyl).
In a certain embodiment, when R2Is C1-6When alkyl, said C1-6Alkyl is C1-4Alkyl (for example, methyl or butyl).
In a certain embodiment, when R3Is C1-6When alkyl, said C1-6Alkyl is C1-4Alkyl (for example, methyl or butyl).
In a certain embodiment, when R4Is C1-6When alkyl, said C1-6Alkyl is C1-4Alkyl (for example, methyl or butyl).
In a certain embodiment, when R4Is hydrogen.
In one embodiment, the anion may be an anion conventional in the art, preferably an anion conventional in the art-R5Wherein R is5Can beBF4Or PF6。
In a certain embodiment, R5Is composed of
In one embodiment, the cation is Preferably is More preferably, it is
In one embodiment, the fluorosulfonyl compound is selected from the following structures:
preferably is
The invention also provides a preparation method of the fluorine-containing sulfonyl compound, which comprises the following steps:
in a first organic solvent, reacting a compound represented by formula 2 and R2-anionic reaction, i.e. reaction;
wherein R is1、R2、R3And R4As defined above.
Wherein, R is2-in the structure of an anion, the anion may be R5(ii) a In the reaction, R2Linking to N to form a cation; wherein R is5Formation of anions-R5。
Wherein, R is2In the structure of anions, e.g. when R2When it is methyl, said R2The anion may have the structure
The reaction conditions of the method for preparing the fluorosulfonyl compound may be those conventional in the art, and the following conditions are particularly selected in the present invention:
wherein the first organic solvent is preferably selected from one or more of acetonitrile, dichloromethane, diethyl ether, tetrahydrofuran, 1, 2-dichloroethane, dimethyl sulfoxide (DMSO), N-dimethylformamide, methyl tert-butyl ether (MTBE), and chloroform, more preferably methyl tert-butyl ether (MTBE).
Wherein the reaction temperature may be (-15) deg.C-20 deg.C, preferably 0 deg.C.
Wherein the progress of the reaction can be monitored by TLC or HPLC, typically in the form ofOr R2-R5When disappeared, it was used as the end point of the reaction. The reaction time may be 0.5 to 8 hours, and more preferably 1 to 4 hours.
Wherein the reaction further comprises a post-treatment step, which may comprise the following operations: concentrating, washing, and removing solvent. The concentration can be carried out by rotary evaporation, and the washing can be carried out by using methyl tert-butyl ether, for example, 3 times; the washed solvent can be directly poured out after the solid is separated out, and the residual solvent can be pumped by an oil pump.
Wherein the reaction further comprises the following steps: in a second organic solvent in the presence of a base,and sulfuryl fluoride (SO)2F2) Reacting to produce saidWherein R is1、R3、R4And R5As defined above.
Said preparation processThe reaction of (a) with (b),
wherein the second organic solvent may be an organic solvent conventional in the art, and is selected from one or more of acetonitrile, dichloromethane, ethyl acetate, benzene, toluene, acetone, 1, 4-dioxane, diethyl ether, tetrahydrofuran, 1, 2-dichloroethane, dimethyl sulfoxide (DMSO), N-dimethylformamide, N-methylpyrrolidone, methyl tert-butyl ether (MTBE), and chloroform, preferably acetonitrile.
Wherein the base may be a base conventional in the art, and may be one or more of an inorganic base (e.g., sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, sodium bicarbonate, and potassium bicarbonate, preferably sodium carbonate) or an organic base (e.g., triethylamine, N-diisopropylethylamine, pyrrole, and pyridine, preferably triethylamine).
Wherein the reaction can be carried out at a temperature of between (-20) DEG C and 35 ℃, preferably room temperature.
Wherein the progress of the reaction can be monitored by TLC or HPLC, typically in the form ofWhen disappeared, it was used as the end point of the reaction. The reaction time may be 0.5 to 48 hours, more preferably 1 to 24 hours, for example 2 to 16 hours.
Wherein the sulfuryl fluoride is in a gaseous state; the introduction method of sulfuryl fluoride is not particularly limited, and may be a gas introduction method which is conventional in the art, and for example, sulfuryl fluoride gas may be introduced by pumping the reaction system to a negative pressure with a water pump and then introducing it into a balloon.
Wherein the reaction further comprises a post-treatment step, the post-treatment step comprising the operations of: filtering, washing filter cake, washing for the first time, extracting, washing for the second time, drying, filtering and concentrating. The washing filter cake can be carried out by adopting dichloromethane or ethyl acetate; the first washing may be performed with water; the extraction can be carried out by using dichloromethane or ethyl acetate; the second washing may be performed using a saturated saline solution; the drying may be performed using anhydrous sodium sulfate or anhydrous magnesium sulfate.
The invention also provides application of the fluorine-containing sulfonyl compound as a fluorine sulfonylation reagent.
The use as a fluorosulfonation reagent can comprise the following steps: reacting a substrate with the fluorine-containing sulfonyl compound; wherein the substrate is a compound containing phenolic hydroxyl, primary amine or secondary amine.
The application of the fluorine sulphonylation reagent, wherein the number of phenolic hydroxyl groups in the phenolic hydroxyl group-containing compound can be one, two or three.
The use as a fluorosulfonation reagent, wherein, when said substrate is a phenolic hydroxyl group-containing compound, the product obtained from the reaction is selected from the group consisting of:
the use as fluorosulfonation reagent, wherein, when said substrate is a primary amine, the product obtained from the reaction is selected from the group consisting of:
the use as fluorosulfonyl reagent, wherein the reaction of said substrate with said fluorosulfonyl compound can be carried out at 0-35 ℃, preferably at room temperature.
The application of the fluorine sulfonyl chemical reagent is that the reaction time of the substrate and the fluorine sulfonyl chemical compound can be 5min-6h, preferably 10min-4h, and more preferably 1h or 2 h.
The use as fluorosulfonyl reagent, wherein the reaction of said substrate with said fluorosulfonyl compound can be carried out in an organic solvent, which can be an organic solvent conventional for this type of reaction, preferably acetonitrile, dichloromethane or ethyl acetate.
The use as a fluorosulfonyl reagent, wherein the reaction of said substrate with said fluorosulfonyl compound is monitored by LC-MS or GC-MS, generally with the disappearance of the substrate as the end point of the reaction.
The use as a fluorosulfonation reagent, wherein the reaction of said substrate with said fluorosulfonyl compound further comprises a post-treatment step, said post-treatment step comprising the following operations: adding water to terminate the reaction, extracting, washing, drying, filtering, concentrating, and removing the solvent. The extraction may be carried out with ethyl acetate, preferably three times; the washing can be carried out by using water and a saturated sodium chloride solution in sequence; the drying can be carried out by adopting anhydrous sodium sulfate; the concentration can be carried out by rotary evaporation; the solvent removal can be carried out by means of an oil pump.
In the present invention, the room temperature may be defined as a room temperature which is conventional in the art, and is preferably 5 to 30 ℃.
In the present invention, the primary amine may be defined as a primary amine which is conventional in the art, and means that one hydrogen in an amine molecule is substituted with a substituent.
In the present invention, the secondary amine may be defined as a secondary amine that is conventional in the art, meaning that two hydrogens in the amine molecule are substituted with substituents.
On the basis of the common knowledge in the field, the above preferred conditions can be combined randomly to obtain the preferred embodiments of the invention.
The reagents and starting materials used in the present invention are commercially available.
The positive progress effects of the invention are as follows:
the fluorine-containing sulfonyl compound is an amphoteric compound, comprises cations and anions, can react with a substrate to efficiently synthesize a fluorine sulfonyl product, has low toxicity, is simple to prepare and convenient to use, and is in a solid stable state at normal temperature; in addition, the compound has extremely wide substrate adaptability, can comprise phenolic compounds and amine compounds, is the only solid form reagent which can realize the chemical transformation at present, and has important academic and application values.
Drawings
FIG. 1 shows an experimental apparatus for preparing sulfuryl fluoride gas, wherein A and B are reaction bottles.
Detailed Description
The invention is further illustrated by the following examples, which are not intended to limit the scope of the invention. The experimental methods without specifying specific conditions in the following examples were selected according to the conventional methods and conditions, or according to the commercial instructions.
An experimental instrument:
1the H NMR spectrum was measured with an Agilent-400(400MHz) NMR spectrometer,1internal standard of H NMR was TMS (. delta.0.00) or CDCl3(δ7.26)。
13The C NMR spectrum was measured with a nuclear magnetic resonance apparatus of the Bruker AM-400(100.7MHz) type,13internal standard of C NMR is CDCl3(δ77.16)、DMSO-d6(δ39.52)、CD3CN(δ1.32)、(CD3)2CO(δ29.84,206.26)。
19The F NMR spectrum was measured with an Agilent-400(376MHz) nuclear magnetic resonance apparatus,19external standard CFCl for F NMR3(δ 0.00), the low field is positive.
LC-MS (ESI) spectra were determined using a Waters ACQUITY UPLC H-Class system and an ACQUITY QDa mass spectrometer (eluent: 0.1% aqueous trifluoroacetic acid and acetonitrile).
GC-MS (EI) spectra were determined by GC-2010Plus and GCMS-QP2010Ultra of SHIMADZU (method: T:. RTM.: T)0＝50℃,t＝3min,ramp＝25℃/min；T1＝100℃,t＝2min,ramp＝10℃/min；T2300 ℃, t 3min) or Agilent 7890A GC System and Agilent 5975C insert MSD System (method: t is0＝80℃,t＝3min,ramp＝20℃/min；T1＝300℃,t＝15min)。
The HRMS spectra were determined on a Finnigan MAT model 8430 mass spectrometer.
Melting points were measured using a M-565 melting point apparatus manufactured by BUCHI.
Experimental reagents and materials:
the column chromatography uses silica gel (300-.
The reagents used were purchased from Shanghai Aladdin Biotechnology, Inc. (Addin), echiei Chemical Industrial development, Inc. (TCI), Shanghai Merlin Biotechnology, Inc. (Macklin), Saen Chemical technology, Inc. (Energy Chemical), Alfa Aesar (China) Chemical Inc. (Alfa Aesar), Shanghai Tatanke technology, Inc. (adamas), Shanghai sub-medicine, Inc., Shanghai Bigdi medicine, technology, Inc., Shanghai Tianlian Chemical engineering, Shanghai Xianshen Biotechnology, Inc., Shanghai Lingyuan Chemical reagents, Inc., or Shanghai reagent, Inc.
The solvent is purchased from Shanghai Michelin Biochemical technology Co., Ltd (Macklin), Shanghai Tantake technology Co., Ltd (adamas), Shanghai Tianlian chemical technology Co., Ltd, Shanghai Dahe Chemicals Co., Ltd, Shanghai Hebang pharmaceutical technology Co., Ltd, and is directly used after purchasing without additional treatment.
In the embodiment of the invention, the Tfo isNamely CF3SO3(ii) a The RT is room temperature.
Example 1
Preparation of 1- (fluorosulfonyl) -2, 3-dimethyl-1H-imidazole trifluoromethanesulfonate
Preparation of Scheme 11- (fluorosulfonyl) -2, 3-dimethyl-1H-imidazole trifluoromethanesulfonate
To a suspension of sodium carbonate (159.1g,1500mmol) in acetonitrile (600mL) at room temperature was added 2-methylimidazole [ compound 1]](49.3g,600mmol), pumping the reaction system to negative pressure by a water pump, and introducing sulfuryl fluoride gas [ Compound 2] into the reaction system by a balloon](18L,730mmol), stirring overnight, TLC (petroleum ether: ethyl acetate: 10:1, product Rf0.44), filtering the reaction solution with silica gel (10-40 mesh), washing the filter cake with dichloromethane (600mL), extracting the filtrate with distilled water (3000mL × 3), combining the aqueous phases, back-extracting with dichloromethane (600mL), combining the organic phases, washing with saturated brine (600mL), drying with anhydrous sodium sulfate, concentrating the filtrate with a rotary evaporator (the boiling point of 2-methyl-1H-imidazole-1-sulfonyl fluoride is low, the temperature is controlled below 20 ℃ during concentration, the pressure is controlled above 140 torr), obtaining the product 2-methyl-1H-imidazole-1-sulfonyl fluoride [ compound 3] as a product]271.1g of a mixed solution of methylene chloride and acetonitrile was quantified by p-toluenesulfonyl fluoride, and the yield of the product was 96.4g and 97.8%. Adding the second component into the mixed solution prepared in the previous step under the protection of nitrogenMethyl chloride (600mL), ice-bath cooling to 0 ℃, dropwise adding methyl trifluoromethanesulfonate (67mL,592mmol) at the speed of 4.5mL/min by using a syringe under the stirring state, naturally melting in the ice-bath and returning to room temperature, reacting for 1 hour, detecting the completion of the reaction by LC-MS, concentrating the reaction liquid by using a rotary evaporator to obtain viscous oily matter, adding methyl tert-butyl ether (500mL), stirring to separate out a solid, pouring out the supernatant, washing the solid by using methyl tert-butyl ether (500mL multiplied by 2), and pumping out the solvent by using an oil pump to obtain a white solid 1- (fluorosulfonyl) -2, 3-dimethyl-1H-imidazole trifluoromethanesulfonate [ compound 4] (compound 1-fluorosulfonyl) -2, 3-dimethyl-](179.6g, 93.2%; 91% overall yield) (Scheme 1).
White solid, m.p.58-60 ℃,179.6g, 91% yield;1H NMR(400MHz,CD3CN)δ7.87(d,J＝2.4Hz,1H),7.56(d,J＝2.8Hz,1H),3.85(s,3H),2.86(s,3H)；13C NMR(100MHz,CD3CN) δ151.4,125.5,122.1,122.0(q,J＝318Hz),37.5,12.9；19F NMR(376MHz,CD3CN)δ61.4(s, 1F),-78.1(s,3F)；LC-MS(tR):0.23min；ESI-MS(m/z):179[M]+,148[M]-(ii) a HRMS (DART, m/z) calculated value C5H8O2N2FS:179.0285[M]+179.0284, actual value; HRMS (DART, m/z) calculated CO3F3S:148.9526[M]-The actual value is 148.9525.
Example 2
Preparation of 1- (fluorosulfonyl) -3-methyl-1H-imidazole trifluoromethanesulfonate
Preparation of Scheme 21- (fluorosulfonyl) -3-methyl-1H-imidazole trifluoromethanesulfonate
To a suspension of sodium carbonate (4.2g,40mmol) in acetonitrile (80mL) at room temperature was added imidazole [ compound 5]](1.36g,20mmol), the reaction system was pumped to negative pressure by a water pump, and sulfuryl fluoride gas [ Compound 2] was introduced into the reaction system through a balloon](0.6L,25 mmol), stirring overnight, TLC (petroleum ether: ethyl acetate 10:1, product R)f0.48), water (200mL) was added to the system to separate the reaction liquid into phases, dichloromethane (200mL × 3) was extracted, and the organic phases were combinedWashing with saturated saline (150mL), drying with anhydrous magnesium sulfate, filtering with diatomaceous earth, concentrating the filtrate to about 40mL (boiling point of 1H-imidazole-1-sulfonyl fluoride is low, temperature is controlled below 28 deg.C, and pressure is controlled above 140 torr) by rotary evaporator to obtain product 1H-imidazole-1-sulfonyl fluoride [ compound 6]]And a mixed solution of dichloromethane and acetonitrile. Adding methyl tert-butyl ether (50mL) into the mixed solution prepared in the above way under the protection of nitrogen, cooling to 0 ℃ in an ice bath, slowly adding methyl trifluoromethanesulfonate (3.28g,20mmol) by using a syringe under the stirring state, removing the ice bath after the dropwise addition is finished, reacting at room temperature for 4 hours, detecting the reaction completion by TLC, concentrating the reaction solution by using a rotary evaporator to obtain a white solid, washing the methyl tert-butyl ether (50mL multiplied by 3), and pumping out the solvent by using an oil pump to obtain a white solid 1- (fluorosulfonyl) -3-methyl-1H-imidazole trifluoromethanesulfonate [ compound 7]](5.3g,84％)(Scheme 2)。
White solid, m.p.67-71 ℃,5.3g, 84% yield;1H NMR(400MHz,CD3CN)δ9.41(s,1H), 8.01(s,1H),7.68(s,1H),3.98(s,3H)；13C NMR(100MHz,CD3CN)δ141.3(s),127.6,121.9 (q,J＝318Hz),122.4,38.5；19F NMR(376MHz,CD3CN)δ61.2(s,1F),-78.1(s,3F).
example 3
Preparation of 1- (fluorosulfonyl) -1H-imidazole hydrogen sulfate
Preparation of Scheme 31- (fluorosulfonyl) -1H-imidazole hydrogen sulfate
To a suspension of sodium carbonate (2.1g,20mmol) in acetonitrile (40mL) at room temperature was added imidazole [ compound 5]](0.68 g,10mmol), the reaction system was pumped to negative pressure by a water pump, and sulfuryl fluoride gas [ Compound 2] was introduced into the reaction system through a balloon](0.4L,16mmol), stirring overnight, TLC (petroleum ether: ethyl acetate 10:1, product R)f= 0.48), the reaction was completed, water (100mL) was added to the system to separate the reaction liquid phases, methylene chloride (80mL × 3) was extracted, the organic phases were combined and washed with saturated brine (60mL), dried over anhydrous magnesium sulfate, filtered over celite, and the filtrate was concentrated by a rotary evaporator to a concentration of20mL (1H-imidazole-1-sulfonyl fluoride has a low boiling point, the temperature during concentration is controlled to be below 28 ℃ and the pressure is controlled to be above 140 torr) to obtain the product 1H-imidazole-1-sulfonyl fluoride [ compound 6]]And a mixed solution of dichloromethane and acetonitrile. Adding methyl tert-butyl ether (20mL) into the mixed solution prepared above under the protection of nitrogen, cooling to 0 deg.C in ice bath, slowly adding concentrated sulfuric acid (0.55mL,10mmol) with a syringe under stirring, removing ice bath after dropwise addition, reacting at room temperature for 4 hr, detecting by TLC to obtain white solid after filter paper filtration, washing with methyl tert-butyl ether (20mL × 3), and pumping off solvent with an oil pump to obtain white solid 1- (fluorosulfonyl) -1H-imidazole hydrogen sulfate [ compound 8]](2.36g,95％)(Scheme 3)。
Setting the temperature on a melting point instrument at 60-120 ℃, increasing the temperature gradient by 1 ℃/min, melting the sample at 94.5 ℃, bubbling at 96 ℃, and eliminating bubbles at 104 ℃ to obtain colorless transparent liquid.
White solid, 2.36g, 95% yield;1H NMR(400MHz,DMSO-d6)δ11.55(br,2H),8.65(s, 1H),8.08(s,1H),7.38(s,1H)；19F NMR(376MHz,DMSO-d6)δ59.7(s,1F).
example 4
Preparation of 2-butyl-1- (fluorosulfonyl) -3-methyl-1H-imidazole trifluoromethanesulfonate
Preparation of Scheme 42-butyl-1- (fluorosulfonyl) -3-methyl-1H-imidazole trifluoromethanesulfonate
To a suspension of sodium carbonate (1.06g,10mmol) in acetonitrile (50mL) at room temperature was added 2-butylimidazo [ compound 9 [)](0.62g,5mmol), the reaction system was pumped to negative pressure by a water pump, and sulfuryl fluoride gas [ Compound 2] was introduced into the reaction system through a balloon](0.25L, 10mmol), stirring overnight, TLC (petroleum ether: ethyl acetate 10:1, product R)fNo. 0.50), the reaction was completed, water (100mL) was added to the system to separate the reaction liquid phases, ethyl acetate (100mL × 3) was extracted, the organic phases were combined and washed with saturated brine (80mL), dried over anhydrous sodium sulfate, filtered through filter paper, the filtrate was concentrated by a rotary evaporator,column chromatography purification (petroleum ether: dichloromethane ═ 5:1) gave 2-butyl-1-H-imidazole-1-sulfonyl fluoride [ compound 10] as a colorless oil](938mg, 88%). 2-butyl-1-H-imidazole-1-sulfonyl fluoride [ compound 10] prepared as above under the protection of nitrogen](938mg, 4.5mmol) was added methyl tert-butyl ether (50mL), cooled to 0 ℃ in an ice bath, while stirring, methyl triflate (0.51mL,5mmol) was slowly added with a syringe, after the addition was completed, the ice bath was removed, the reaction was carried out at room temperature for 4 hours, followed by TLC, the reaction solution was concentrated by a rotary evaporator, washed with methyl tert-butyl ether (50 mL. times.3), and the solvent was pumped off by an oil pump to obtain 2-butyl-1- (fluorosulfonyl) -3-methyl-1H-imidazole trifluoromethanesulfonate [ Compound 11] as a colorless oil](0.2g, 12％)(Scheme 4)。
Colorless oil, 0.2g, 12% yield;1H NMR(400MHz,CDCl3)δ7.79(d,J＝5.7Hz,2H),4.03 (s,3H),3.29(t,J＝8Hz,2H),1.71(quin,J＝7.6Hz,2H),1.52(sext,J＝7.6Hz,2H),1.00(t,J ＝7.2Hz,3H)；19F NMR(376MHz,CDCl3)δ62.7(s,0.7F),-78.7(s,3F).
example 5
Preparation of 1- (fluorosulfonyl) -2-isopropyl-3-methyl-1H-imidazole trifluoromethanesulfonate
Preparation of Scheme 51- (fluorosulfonyl) -2-isopropyl-3-methyl-1H-imidazole trifluoromethanesulfonate
To a suspension of sodium carbonate (6.78g,64mmol) in acetonitrile (100mL) at room temperature was added 2-isopropylimidazole [ compound 12]](3.5g,32mmol), the reaction system was pumped to negative pressure by a water pump, and sulfuryl fluoride gas [ Compound 2] was introduced into the reaction system through a balloon](1L,40mmol), stirring overnight, TLC (petroleum ether: ethyl acetate: 10:1, product Rf0.53), adding water (200mL) into the system to separate phases of the reaction solution, extracting with ethyl acetate (200 mL. times.3), combining organic phases, washing with saturated saline (150mL), drying with anhydrous sodium sulfate, filtering with filter paper, concentrating the filtrate by a rotary evaporator, and purifying by column chromatography (silica gel 300-400 mesh, petroleum ether: ethyl acetate 10:1) to give 2-isopropyl-1-H-imidazole-1-sulfonic acid as a colorless oilAcyl fluoride [ compound 13]](2.2g,35％)(Scheme 5)。
Colorless oil, 2.2g, 35% yield;1HNMR(400MHz,CDCl3)δ7.32(s,1H),7.03(s,1H),3.47 (sept,J＝6.8Hz,1H),1.38(d,J＝6.8Hz,6H)；19F NMR(376MHz,CDCl3)δ59.3(s,1F).
the methylation reaction was disordered and 1- (fluorosulfonyl) -2-isopropyl-3-methyl-1H-imidazole trifluoromethanesulfonate [ compound 14] was not obtained.
Example 6
Preparation of 1- (fluorosulfonyl) -2, 3-dimethyl-1H-benzimidazole trifluoromethanesulfonate
Preparation of Scheme 61- (fluorosulfonyl) -2, 3-dimethyl-1H-benzimidazole trifluoromethanesulfonate
To a suspension of sodium carbonate (6.3g,60mmol) in acetonitrile (50mL) at room temperature was added 2-methylbenzimidazole [ compound 15 ]](3.96g,30mmol), the reaction system was pumped to negative pressure by a water pump, and sulfuryl fluoride gas [ Compound 2] was introduced into the reaction system through a balloon](1L,40mmol), stirring overnight, TLC (petroleum ether: ethyl acetate: 10:1, product Rf0.50), adding water (100mL) into the system to separate phases of the reaction solution, extracting with ethyl acetate (100 mL. times.3), combining organic phases, washing with saturated saline (80mL), drying with anhydrous sodium sulfate, filtering with filter paper, concentrating the filtrate by a rotary evaporator, and purifying by column chromatography (silica gel 300-400 mesh, petroleum ether: ethyl acetate 10:1) to give 2-methyl-1H-benzimidazole-1-sulfonyl fluoride [ compound 16) as a white solid](0.89g,14％)。
White solid, 0.89g, 14% yield;1H NMR(400MHz,CDCl3)δ7.81(m,1H),7.74(m,1H), 7.42(m,2H),2.86(s,3H)；19F NMR(376MHz,CDCl3)δ58.3(s).
to 2-methyl-1H-benzimidazole-1-sulfonyl fluoride [ compound 16] (0.89g,4mmol) prepared above was added methyl tert-butyl ether (50mL) under nitrogen, the mixture was cooled to 0 ℃ in an ice bath, methyl trifluoromethanesulfonate (0.443g,4mmol) was slowly added by a syringe under stirring, the ice bath was removed after completion of dropwise addition, the reaction was allowed to react at room temperature for 4 hours, followed by TLC, the reaction mixture was concentrated by a rotary evaporator, washed with methyl tert-butyl ether (50mL × 3), and the solvent was pumped out by an oil pump to obtain 1- (fluorosulfonyl) -2, 3-dimethyl-1H-benzimidazole trifluoromethanesulfonate [ compound 17] (1.17g, 78%) as a white solid (Scheme 6).
White solid, 1.17g, 78% yield;1H NMR(400MHz,CD3CN)δ8.10(s,1H),7.98(s,1H), 7.87(s,2H),4.10(s,3H),3.13(s,3H)；19F NMR(376MHz,CD3CN)δ62.8(s,1F),-78.1(s, 3F).
example 7
Preparation of 2-chloro-1- (fluorosulfonyl) -3-methyl-1H-benzimidazole trifluoromethanesulfonate
Preparation of Scheme 72-chloro-1- (fluorosulfonyl) -3-methyl-1H-benzimidazole trifluoromethanesulfonate
To a suspension of sodium carbonate (6.3g,60mmol) in acetonitrile (50mL) at room temperature was added 2-chlorobenzimidazole [ compound 18 ]](4.2g,30mmol), the reaction system was pumped to negative pressure by a water pump, and sulfuryl fluoride gas [ Compound 2] was introduced into the reaction system through a balloon](1L,40mmol), stirring overnight, TLC (petroleum ether: ethyl acetate: 20:1, product Rf0.64), adding water (100mL) into the system to separate phases of the reaction solution, extracting with ethyl acetate (100 mL. times.3), combining organic phases, washing with saturated saline (80mL), drying with anhydrous sodium sulfate, filtering with filter paper, concentrating the filtrate by a rotary evaporator, and purifying by column chromatography (silica gel 300-400 mesh, petroleum ether: ethyl acetate ═ 20:1) to give 2-chloro-1H-benzimidazole-1-sulfonyl fluoride [ compound 19] as a white solid](2.61g,39％)(Scheme 7)。
White solid, 2.61g, 39% yield;1H NMR(400MHz,CDCl3)δ7.83(m,1H),7.75(m,1H), 7.49(m,2H)；19F NMR(376MHz,CDCl3)δ60.4(s,1F).
the methylation reaction is disordered, and the 2-chloro-1- (fluorosulfonyl) -3-methyl-1H-benzimidazole trifluoromethanesulfonate [ compound 20] is not obtained.
Example 8
Preparation of 2-ethyl-1- (fluorosulfonyl) -3, 4-dimethyl-1H-imidazole trifluoromethanesulfonate
Preparation of Scheme 82-ethyl-1- (fluorosulfonyl) -3, 4-dimethyl-1H-imidazole trifluoromethanesulfonate
To a suspension of sodium carbonate (2.1g,20mmol) in acetonitrile (50mL) at room temperature was added 2-ethyl-4-methylimidazole [ compound 21 ]](1.1g,10mmol), the reaction system was pumped to negative pressure by a water pump, and sulfuryl fluoride gas [ Compound 2] was introduced into the reaction system through a balloon](0.4L,16mmol), stirring overnight, TLC (petroleum ether: ethyl acetate 10:1, product R)f0.50), adding water (100mL) into the system to separate phases of the reaction solution, extracting with ethyl acetate (80 mL. times.3), combining organic phases, washing with saturated saline (60mL), drying with anhydrous sodium sulfate, filtering with filter paper, concentrating the filtrate by a rotary evaporator, and purifying by column chromatography (silica gel 300-400 mesh, petroleum ether: ethyl acetate 10:1) to give 2-ethyl-4-methyl-1-H-imidazole-1-sulfonyl fluoride [ compound 22) as a white solid](1.27g, 66%). 2-Ethyl-4-methyl-1-H-imidazole-1-sulfonyl fluoride [ compound 22 ] prepared as above under nitrogen protection](1.27g,6.6mmol) was added to methyl tert-butyl ether (50mL), the mixture was cooled to 0 ℃ in an ice bath, methyl triflate (0.73mL,6.6mmol) was slowly added with stirring using a syringe, the ice bath was removed after the dropwise addition was completed, the mixture was reacted at room temperature for 4 hours, the reaction was followed by TLC, the reaction solution was concentrated by a rotary evaporator, and methyl tert-butyl ether (50 mL. times.3) was washed and the solvent was pumped off by an oil pump to obtain 2-ethyl-1- (fluorosulfonyl) -3, 4-dimethyl-1H-imidazole trifluoromethanesulfonate as a white solid [ Compound 23] (Compound 23)](2.22g,96％)(Scheme 8)。
White solid, 2.22g, 96% yield;1H NMR(400MHz,CDCl3)δ7.52(s,1H),3.89(s,3H),3.38 (q,J＝7.6Hz,2H),2.42(s,3H),1.41(t,J＝7.6Hz,3H)；19F NMR(376MHz,CDCl3)δ62.3 (s,1F),-78.6(s,3F).
example 9
Preparation of 2,4, 5-tribromo-1H-imidazole-1-sulfonyl fluoride
Preparation of Scheme 92, 4, 5-tribromo-1H-imidazole-1-sulfonyl fluoride
2,4, 5-tribromoimidazo [ compound 24] (1.5g,5mmol) was added to a suspension of sodium carbonate (1.06g,10mmol) in acetonitrile (50mL) at room temperature, and after the reaction system was pumped to negative pressure by a water pump, sulfuryl fluoride gas [ compound 2] was introduced into the reaction system by a balloon, and stirred overnight without reaction (Scheme 9).
Example 10
Preparation of 2-chloro-5-nitro-1H-imidazole-1-sulfonyl fluoride
Preparation of Scheme 102-chloro-5-nitro-1H-imidazole-1-sulfonyl fluoride
2-chloro-4-nitroimidazo [ compound 26] (730mg,5mmol) was added to a suspension of sodium carbonate (1.06g,10mmol) in acetonitrile (50mL) at room temperature, and after the reaction system was pumped to a negative pressure by a water pump, sulfuryl fluoride gas [ compound 2] was introduced into the reaction system via an air balloon and stirred overnight without reaction (Scheme 10).
Example 11
Preparation of 2-nitro-1H-imidazole-1-sulfonyl fluoride
Preparation of Scheme 112-nitro-1H-imidazole-1-sulfonyl fluoride
2-Nitroimidazol [ compound 28] (560mg,5mmol) was added to a suspension of sodium carbonate (1.06g,10mmol) in acetonitrile (50mL) at room temperature, and after the reaction system was pumped to a negative pressure by a water pump, sulfuryl fluoride gas [ compound 2] was introduced into the reaction system by a balloon and stirred overnight without reaction (Scheme 11).
Example 12
Preparation of 1- (fluorosulfonyl) -1H-imidazole-2-carboxylic acid methyl ester
Preparation of Scheme 121- (fluorosulfonyl) -1H-imidazole-2-carboxylic acid methyl ester
To a suspension of sodium carbonate (1.06g,10mmol) in acetonitrile (50mL) was added methyl 1H-imidazole-2-carboxylate [ compound 28] (630mg,5mmol) at room temperature, the reaction system was pumped to negative pressure with a water pump, and then sulfuryl fluoride gas [ compound 2] was introduced with a balloon, and stirred overnight, and less than 2% of the starting material was reacted (Scheme 12).
Example 13
Preparation of sulfuryl fluoride gas
Preparation of Scheme 13 sulfuryl fluoride gas
The apparatus for producing sulfuryl fluoride gas is shown in FIG. 1.
As shown in FIG. 1, potassium fluoride (581mg,10mmol) was added to flask A and 4-cinnamyl phenol [ compound 32] was added to flask B at room temperature](212mg,1mmol) and a buffer balloon were inserted, the reaction system was pumped down to negative pressure with a water pump, then acetonitrile (5mL) solution of triethylamine (152mg,1.5mmol) was injected into flask B, and 1- (fluorosulfonyl) -2, 3-dimethyl-1H-imidazole trifluoromethanesulfonate [ Compound 4] was injected into flask A](3.283g,10mmol) in acetonitrile (10mL) for 1h, TLC (petroleum ether: ethyl acetate 10:1, product R)f0.61), monitoring a gas sulfuryl fluoride signal and a 4- (2-phenyl-2-propyl) phenoxysulfonyl fluoride signal in a B bottle reaction solution by a fluorine spectrum, and purifying by column chromatography (silica gel 300-: ethyl acetate ═ 30:1) to give 4- (2-phenyl-2-propyl) phenoxysulfonyl fluoride [ compound 33] as a colorless liquid](288mg,97％)。(Scheme 13)。
Colorless liquid, 288mg, 97% yield;1H NMR(400MHz,CDCl3)δ7.33-7.19(m,9H),1.69(s, 6H)；13C NMR(100MHz,CDCl3)δ151.8,149.6,148.1,128.9,128.4,126.8,126.2,120.3,43.0, 30.8；19F NMR(376MHz,CDCl3)δ36.8(s,1F)；GC-MS(tR):18.4min；EI-MS(m/z):294[M]+.
example 14
Preparation of 4- (2-phenyl-2-propyl) phenoxysulfonyl fluoride
Preparation of Scheme 144- (2-phenyl-2-propyl) phenoxysulfonyl fluoride
Triethylamine (220. mu.L, 1.59mmol) was added to 4-cinnamylphenol [ compound 32] at room temperature](225mg,1.04mmol) acetonitrile (1mL), and after stirring for 10min, 1- (fluorosulfonyl) -2-3-dimethyl-1H-imidazole trifluoromethanesulfonate [ compound 4]]A solution of (448mg,1.27mmol) acetonitrile (1mL) was added to the system in one portion and reacted for 1h under argon protection, TLC (petroleum ether: ethyl acetate 10:1, product Rf0.61) the reaction was followed. Purifying by column chromatography (silica gel 300-400 mesh, petroleum ether: ethyl acetate: 30:1) to obtain colorless liquid 4- (2-phenyl-2-propyl) phenoxysulfonyl fluoride [ compound 33-](293mg,95％)(scheme 14)。
Colorless liquid, 293mg, 95% yield;1H NMR(400MHz,CDCl3)δ7.32-7.20(m,9H),1.69(s, 6H)；13C NMR(100MHz,CDCl3)δ151.8,149.6,148.1,128.9,128.3,126.8,126.2,120.3,43.0, 30.7；19F NMR(376MHz,CDCl3)δ36.8(s,1F)；GC-MS(tR):18.4min；EI-MS(m/z):294[M]+.
example 15
Preparation of 2, 2-propylbis- (4, 1-phenylene) -dioxysulfonyl fluoride
Preparation of Scheme 152, 2-propylbis- (4, 1-phenylene) -dioxysulfuryl fluoride
Triethylamine (220. mu.L, 1.59mmol) was added to bisphenol A [ Compound 34 ] at room temperature](120mg,0.52mmol) acetonitrile (1mL) solution, after stirring for 10min, 1- (fluorosulfonyl) -2-3-dimethyl-1H-imidazole trifluoromethanesulfonate [ compound 4]](448mg,1.27mmol) acetonitrile (1mL) solution was added to the system in one portionReacted for 1h under argon protection, TLC (petroleum ether: ethyl acetate 10:1, product R)f0.43), the reaction was followed and purified by column chromatography (silica gel 300-: ethyl acetate ═ 30:1) to give 2, 2-propylbis- (4, 1-phenylene) -dioxosulfonyl fluoride [ compound 35] as a white solid](169mg,82％)(scheme 15)。
White solid, m.p.48.2-49.5 ℃,169mg, 82% yield;1H NMR(400MHz,CDCl3)δ7.32-7.25 (m,8H),1.70(s,6H)；13C NMR(100MHz,CDCl3)δ150.6,148.3,128.9,120.7,43.0,30.8；19F NMR(376MHz,CDCl3)δ37.0(s,2F)；GC-MS(tR):22.0min；EI-MS(m/z):392[M]+.
example 16
Preparation of sulfonyl-bis (4, 1-phenylene) dioxysulfonyl fluoride
Preparation of Scheme 16 sulfonyl di (4, 1-phenylene) dioxysulfonyl fluoride
Triethylamine (220. mu.L, 1.59mmol) was added to bisphenol S [ Compound 36] at room temperature](130mg,0.52mmol) acetonitrile (1mL) solution, after stirring for 10min, 1- (fluorosulfonyl) -2-3-dimethyl-1H-imidazole trifluoromethanesulfonate [ compound 4]]A solution of (448mg,1.27mmol) acetonitrile (1mL) was added to the system in one portion and reacted for 1h under argon protection, TLC (petroleum ether: ethyl acetate 4:1, product Rf0.38), the reaction was followed and purified by column chromatography (silica gel 300-: ethyl acetate 4:1) to give sulfonyl bis (4, 1-phenylene) dioxysulfonyl fluoride [ compound 37] as a white solid](166 mg,77％)(scheme 16)。
White solid, m.p.125.0-126.1 ℃,166mg, 77% yield;1H NMR(400MHz,CDCl3)δ8.10(d, J＝8.0Hz,4H),7.54(d,J＝8.0Hz,4H)；13C NMR(100MHz,CDCl3)δ153.0,141.3,130.7, 122.5；19F NMR(376MHz,CDCl3)δ39.0(s,2F)；GC-MS(tR):23.6min；EI-MS(m/z):414 [M]+.
example 17
Preparation of (1,1 '-biphenyl) -4, 4' -disulfonyl fluoride
Preparation of Scheme 17(1,1 '-biphenyl) -4, 4' -disulfonyl fluoride
Triethylamine (440. mu.L, 3.17mmol) was added to biphenol [ compound 38] at room temperature](198mg,1.04mmol) acetonitrile (1mL) solution, after stirring for 10min, 1- (fluorosulfonyl) -2-3-dimethyl-1H-imidazole trifluoromethanesulfonate [ compound 4]](840mg,2.56mmol) acetonitrile (1mL) solution was added to the system in one portion and reacted for 1h under argon protection, TLC (petroleum ether: ethyl acetate ═ 10:1, product Rf0.53), the reaction was followed and purified by column chromatography (silica gel 300-: ethyl acetate 10:1) to give (1,1 '-biphenyl) -4, 4' -disulfonyl fluoride [ compound 39] as a pale green solid](294mg,81％)(scheme 17)。
Light green solid, m.p.95.3-96.6 ℃,294mg, 81% yield;1H NMR(400MHz,CDCl3)δ7.65(d, J＝8.8Hz,4H),7.45(d,J＝8.8Hz,4H)；13C NMR(100MHz,CDCl3)δ150.0,140.1,129.3, 121.7；19F NMR(376MHz,CDCl3)δ+37.4(s,2F)；GC-MS(tR):20.4min,EI-MS(m/z):350 [M]+(ii) a HRMS (EI, m/z) calculated C12H8O6F2S2:349.9730[M]+The actual value is 349.9729.
Example 18
Preparation of 2, 7-naphthyl-disulfonyl fluoride
Preparation of Scheme 182, 7-naphthyl-disulfonyl fluoride
Triethylamine (440. mu.L, 3.17mmol) was added to 2, 7-dihydroxynaphthalene [ compound 40] at room temperature](169mg,1.04 mmol) acetonitrile (1mL), and after stirring for 10min, 1- (fluorosulfonyl) -2-3-dimethyl-1H-imidazole trifluoromethanesulfonate [ compound 4]](840mg,2.56mmol) acetonitrile (1mL) solution was added to the system in one portion and under argonReaction for 1h under protection of gas, TLC (petroleum ether: ethyl acetate ═ 10:1, product Rf0.54), and column chromatography purification (silica gel 300-: ethyl acetate 10:1) to give 2, 7-naphthyl-disulfonyl fluoride [ compound 41] as a white solid](253mg,75％)(scheme 18)。
White solid, m.p.122.7-124.3 ℃,253mg, 75% yield;1H NMR(400MHz,DMSO-d6)δ8.40 (d,J＝2.0Hz,2H),8.34(s,1H),8.31(s,1H),7.88(d,J＝2.0Hz,1H),7.86(d,J＝2.0Hz,1H)；13C NMR(100MHz,DMSO-d6)δ148.3,133.3,131.5,120.9,119.5；19F NMR(376MHz, DMSO-d6)δ+39.8(s,2F)；GC-MS(tR):17.9min,EI-MS(m/z):324[M]+.
example 19
Preparation of (8R,9S,13S,14S,17R) -17-ethynyl-17-hydroxy-13-methyl-7, 8,9,11,12,13,14,15,16, 17-decahydro-6H-cyclopenta [ a ] -3-phenanthreneoxysulfonyl fluoride
Preparation of Scheme 19(8R,9S,13S,14S,17R) -17-ethynyl-17-hydroxy-13-methyl-7, 8,9,11,12,13,14,15,16, 17-decahydro-6H-cyclopenta [ a ] -3-phenanthrene oxysulfonyl fluoride
Triethylamine (220. mu.L, 1.59mmol) was added to ethinylestradiol [ Compound 42] at room temperature](315mg,1.04mmol) acetonitrile (1mL), after stirring for 10min, 1- (fluorosulfonyl) -2-3-dimethyl-1H-imidazole trifluoromethanesulfonate [ compound 4]]A solution of (448mg,1.27mmol) acetonitrile (1mL) was added to the system in one portion and reacted for 1h under argon protection, TLC (petroleum ether: ethyl acetate 4:1, product Rf0.42), and purified by column chromatography (silica gel 300-: ethyl acetate 4:1) to give (8R,9S,13S,14S,17R) -17-ethynyl-17-hydroxy-13-methyl-7, 8,9,11,12,13,14,15,16, 17-decahydro-6H-cyclopenta [ a ] as a white solid]-3-phenanthrene oxysulfonyl fluoride [ compound 43](349mg, 88％)(scheme 19)。
White solid, m.p.44.9-48.1 ℃,349mg, 88% yield;1H NMR(400MHz,CDCl3)δ7.37(d,J ＝8.0Hz,1H),7.09(d,J＝8.0Hz,1H),7.04(s,1H),2.92-2.89(m,2H),2.61(s,1H),2.39-2.25 (m,3H),2.06-1.91(m,3H),1.83-1.68(m,4H),1.57-1.34(m,4H),0.89(s,3H)；13C NMR(100 MHz,CDCl3)δ148.0,141.0,139.6,127.3,120.6,117.6,87.4,79.7,74.2,49.4,47.0,43.6,38.9, 38.7,32.6,29.5,26.7,26.1,22.7,12.7；19F NMR(376MHz,CDCl3)δ36.8(s,1F)；GC-MS(tR): 26.6min；EI-MS(m/z):378[M]+.
example 20
Preparation of (8R,9S,13S,14S) -13-methyl-17-oxo-7, 8,9,11,12,13,14,15,16, 17-decahydro-6H-cyclopenta [ a ] -3-phenanthrenesulfonyl fluoride
Preparation of Scheme 20(8R,9S,13S,14S) -13-methyl-17-oxo-7, 8,9,11,12,13,14,15,16, 17-decahydro-6H-cyclopenta [ a ] -3-phenanthrene oxysulfonyl fluoride
Triethylamine (220. mu.L, 1.59mmol) was added to estrone [ Compound 44] at room temperature](288mg,1.04mmol) acetonitrile (1mL), and after stirring for 10min, 1- (fluorosulfonyl) -2-3-dimethyl-1H-imidazole trifluoromethanesulfonate [ Compound 4]]A solution of (448mg,1.27mmol) acetonitrile (1mL) was added to the system in one portion and reacted for 1h under argon protection, TLC (petroleum ether: ethyl acetate 4:1, product Rf0.43), the reaction was followed and purified by column chromatography (silica gel 300-: ethyl acetate 4:1) to give (8R,9S,13S,14S) -13-methyl-17-oxo-7, 8,9,11,12,13,14,15,16, 17-decahydro-6H-cyclopenta [ a ] as a white solid]-3-phenanthrene oxysulfonyl fluoride [ compound 45](295mg,80％) (scheme 20)。
White solid, m.p.108.8-111.3 ℃,295mg, 80% yield;1H NMR(400MHz,CDCl3)δ7.37(d, J＝8.0Hz,1H),7.10(d,J＝8.0Hz,1H),7.06(s,1H),2.97-2.94(m,2H),2.56-2.49(m,1H),2.44-2.39(m,1H),2.33-2.27(m,1H),2.21-1.98(m,4H),1.69-1.42(m,6H),0.92(s,3H)；13C NMR(100MHz,CDCl3)δ220.1,148.0,140.5,139.4,127.2,120.5,117.6,50.2,47.7,43.9,37.6, 35.6,31.4,29.2,25.9,25.5,21.4,13.6；19F NMR(376MHz,CDCl3)δ36.9(s,1F)；GC-MS(tR): 26.1min；EI-MS(m/z):352[M]+(ii) a HRMS (EI, m/z) calculated C18H21O4FS:352.1145[M]+352.1143, actual value;
example 21
Preparation of (8R,9S,13S,14S,17S) -17-hydroxy-13-methyl-7, 8,9,11,12,13,14,15,16, 17-decahydro-6H-cyclopenta [ a ] -3-phenanthrenesulfonyl fluoride
Preparation of Scheme 21(8R,9S,13S,14S,17S) -17-hydroxy-13-methyl-7, 8,9,11,12,13,14,15,16, 17-decahydro-6H-cyclopenta [ a ] -3-phenanthrene oxysulfonyl fluoride
Triethylamine (220. mu.L, 1.59mmol) was added to beta-estradiol [ compound 46] at room temperature](292mg,1.04mmol) acetonitrile (1mL) solution, after stirring for 10min, 1- (fluorosulfonyl) -2-3-dimethyl-1H-imidazole trifluoromethanesulfonate [ compound 4]]A solution of (448mg,1.27mmol) acetonitrile (1mL) was added to the system in one portion and reacted for 1h under argon protection, TLC (petroleum ether: ethyl acetate 4:1, product Rf0.38), the reaction was followed and purified by column chromatography (silica gel 300-: ethyl acetate 4:1) to give (8R,9S,13S,14S,17S) -17-hydroxy-13-methyl-7, 8,9,11,12,13,14,15,16, 17-decahydro-6H-cyclopenta [ a ] a pale yellow solid]-3-phenanthrene oxysulfonyl fluoride [ compound 47](305mg,82％) (scheme 21)。
Light yellow solid, m.p.100.2-104.0 ℃,305mg, 82% yield;1H NMR(400MHz,CDCl3)δ7.36 (d,J＝8.8Hz,1H),7.08(d,J＝8.0Hz,1H),7.03(s,1H),3.74(t,J＝8.0Hz,1H),2.91-2.88(m, 2H),2.34-2.09(m,3H),1.99-1.90(m,2H),1.75-1.68(m,1H),1.57-1.17(m,8H),0.79(s,3H)；13C NMR(100MHz,CDCl3)δ147.9,141.2,139.7,127.3,120.5,117.5,81.5,49.9,44.0,43.1, 38.2,36.5,30.3,29.4,26.7,26.1,23.0,11.0；19F NMR(376MHz,CDCl3)δ36.8(s,1F)；GC- MS(tR):26.0min；EI-MS(m/z):354[M]+(ii) a HRMS (EI, m/z) calculated C18H23O4FS:354.1301 [M]+The actual value is 354.1293.
Example 22
(E) Preparation of (E) -4- (3, 5-dimethoxystyryl) phenoxysulfonyl fluoride
Preparation of Scheme 22(E) -4- (3, 5-dimethoxystyryl) phenoxysulfonyl fluoride
Triethylamine (220. mu.L, 1.59mmol) was added to pterostilbene [ compound 48] at room temperature](272mg,1.04mmol) acetonitrile (1mL), after stirring for 10min, 1- (fluorosulfonyl) -2-3-dimethyl-1H-imidazole trifluoromethanesulfonate [ Compound 4]]A solution of (448mg,1.27mmol) acetonitrile (1mL) was added to the system in one portion and reacted for 1h under argon protection, TLC (petroleum ether: ethyl acetate 4:1, product Rf0.43), the reaction was followed and purified by column chromatography (silica gel 300-: ethyl acetate ═ 4:1, 3:1) to give (E) -4- (3, 5-dimethoxystyryl) phenoxysulfonyl fluoride [ compound 49 ] as a pale yellow solid](309mg,87％)(scheme 22)。
Pale yellow solid, m.p.80.1-81.1 ℃,309mg, 87% yield;1H NMR(400MHz,CDCl3)δ7.58(d, J＝8.0Hz,2H),7.33(d,J＝8.0Hz,2H),7.05(s,2H),6.67(s,2H),6.43(s,1H),3.84(s,6H)；13C NMR(100MHz,CDCl3)δ161.0,149.0,138.5,137.8,130.8,128.1,126.8,121.0,104.8, 100.3,55.2；19F NMR(376MHz,CDCl3)δ37.1(s,1F)；GC-MS(tR):24.9min；EI-MS(m/z): 338[M]+(ii) a HRMS (EI, m/z) calculated C16H15O5FS:338.0624[M]+The actual value is 338.0619.
Example 23
(E) Preparation of (E) -4- (3-oxo-3-phenylpropenyl) phenylsulfonyl fluoride
Preparation of Scheme 23(E) -4- (3-oxo-3-phenylpropenyl) phenylsulfonyl fluoride
Triethylamine (220. mu.L, 1.59mmol) was added to 4-hydroxychalcone [ compound 50 ] at room temperature](241mg,1.04 mmol) acetonitrile (1mL), stirring for 10min, and adding 1- (fluorosulfonyl) -2-3-dimethyl-1H-imidazole trifluoromethanesulfonate [ compound 4]](421mg,1.28mmol) acetonitrile (1mL) solution was added to the system in one portion and reacted for 1h under argon protection, TLC (petroleum ether: ethyl acetate ═ 10:1, product R)f0.42), and purified by column chromatography (silica gel 300-: ethyl acetate ═ 10:1) to give (E) -4- (3-oxo-3-phenylpropenyl) phenylsulfonyl fluoride [ compound 51 ] as a pale green solid](262mg,82％)(scheme 23)。
Light green solid, m.p.92.8-94.2 ℃,262mg, 82% yield;1H NMR(400MHz,CDCl3)δ8.02(d, J＝8.0Hz,2H),7.81-7.74(m,3H),7.62(t,J＝7.4Hz,1H),7.56-7.51(m,3H),7.41(d,J＝8.0 Hz,2H)；13C NMR(100MHz,CDCl3)δ150.0,150.9,142.2,137.8,135.6,133.3,130.3,128.8, 128.6,124.0,121.6；19F NMR(376MHz,CDCl3)δ+37.8(s,1F)；GC-MS(tR):22.9min,EI-MS (m/z):306[M]+(ii) a HRMS (EI, m/z) calculated C15H11O4FS:306.0362[M]+The actual value is 306.0369.
Example 24
Preparation of 5-methyl-3- (-2-pyridyl) -5H-benzo [5,6] [1,2] thiazinyl [3,4-e ] [1,2,3] oxathiazin-4 (3H) -one-2, 2,6, 6-tetraoxide
Preparation of Scheme 245-methyl-3- (-2-pyridyl) -5H-benzo [5,6] [1,2] thiazinyl [3,4-e ] [1,2,3] oxathiazin-4 (3H) -one-2, 2,6, 6-tetraoxide
Triethylamine (132. mu.L, 0.95mmol) was added to piroxicam [ compound 52 ] at room temperature](210mg,0.62mmol) acetonitrile (1mL) solution, after stirring for 10min, 1- (fluorosulfonyl) -2-3-dimethyl-1H-imidazole trifluoromethanesulfonate [ compound 4]](268mg,0.76mmol) acetonitrile (1mL) solution was added to the system in one portion and reacted for 1h under argon protection, TLC (petroleum ether: ethyl acetate ═ 1:1, product R)f0.42), and purified by column chromatography (silica gel 300-: ethyl acetate 1:1) to obtainTo pale yellow solid 5-methyl-3- (-2-pyridyl) -5H-benzo [5,6]][1,2]Thiazinyl [3,4-e ]][1,2,3]Oxazin-4 (3H) -one-2, 2,6, 6-tetraoxide [ Compound 53 ]](138mg,56％)(scheme 24)。
Pale yellow solid, m.p.197.3-200.9 ℃,138mg, 56% yield;1H NMR(400MHz,CDCl3)δ8.69 (s,1H),8.03(t,J＝8.0Hz,2H),7.96(t,J＝8.0Hz,1H),7.89(s,2H),7.50-7.48(m,2H),3.29 (s,3H)；13C NMR(100MHz,CDCl3)δ157.1,149.9,146.7,145.5,139.3,135.1,134.2,133.1, 126.1,125.2,124.4,123.5,123.5,120.3,36.6；19F NMR(376MHz,CDCl3)no signal；LC-MS (tR):2.7min；ESI-MS(m/z):394.03[MH]+(ii) a HRMS (ESI, m/z) calculated value C15H12O6N3S2: 394.0162[MH]+The actual value is 394.0171.
Example 25
Preparation of 3- (3-chloro-4- (4-chlorophenoxy) phenyl) -6-8 diiodobenzene [ e ] [1,2,3] oxathiazin-4 (3H) -one-2, 2-dioxide
Preparation of Scheme 253- (3-chloro-4- (4-chlorophenoxy) phenyl) -6-8 diiodobenzene [ e ] [1,2,3] oxathiazin-4 (3H) -one-2, 2-dioxide
Triethylamine (85. mu.L, 0.61mmol) was added to rafoxanide [ compound 54 ] at room temperature](256mg,0.40mmol) acetonitrile (1mL) solution, after stirring for 10min, 1- (fluorosulfonyl) -2-3-dimethyl-1H-imidazole trifluoromethanesulfonate [ compound 4]](172mg,0.49mmol) acetonitrile (1mL) solution was added to the system in one portion and reacted for 1h under argon protection, TLC (petroleum ether: ethyl acetate ═ 10:1, product R)f0.57), the reaction was followed and purified by column chromatography (silica gel 300-: ethyl acetate 30:1) to give 3- (3-chloro-4- (4-chlorophenoxy) phenyl) -6-8 diiodobenzene [ e ] as a white solid][1,2,3]Oxazin-4 (3H) -one-2, 2-dioxide [ Compound 55 ]](154mg,56％)(scheme 25)。
White solid, m.p.183.0-183.8 ℃,154mg, 56% yield;1H NMR(400MHz,CDCl3)δ8.48(d, J＝2.0Hz,1H),8.42(d,J＝2.0Hz,1H),7.55(d,J＝2.8Hz,1H),7.39-7.38(m,1H),7.37-7.35 (m,1H),7.27-7.24(m,1H),7.04-6.98(m,3H)；13C NMR(100MHz,CDCl3)δ158.7,155.1, 154.1,153.6,150.2,139.4,132.0,130.3,130.1,129.2,126.2,126.0,120.8,119.6,119.1,91.6, 86.7；19F NMR(376MHz,CDCl3) no signal; HRMS (DART, m/z) calculated value C19H10O5NCl2I2S: 687.7741[MH]+The actual value is 687.7732.
Example 26
Preparation of (S) -4-ethyl-4-hydroxy-3, 14-dioxo-3, 4,12, 14-tetrahydro-1H-pyrone [3 ', 4': 6,7] indolyl [1,2-b ] -9-quinolinylsulfonyl fluoride
Preparation of Scheme 26(S) -4-ethyl-4-hydroxy-3, 14-dioxo-3, 4,12, 14-tetrahydro-1H-pyrone [3 ', 4': 6,7] indolyl [1,2-b ] -9-quinolinylsulfonyl fluoride
Triethylamine (440. mu.L, 3.17mmol) was added to (S) -10-hydroxycamptothecin [ Compound 56 ] at room temperature](194mg, 0.52mmol) acetonitrile (1mL) solution, after stirring for 10min, 1- (fluorosulfonyl) -2-3-dimethyl-1H-imidazole trifluoromethanesulfonate [ Compound 4]](840mg,2.56mmol) acetonitrile (1mL) solution was added to the system in one portion and reacted for 1h under argon protection, TLC (petroleum ether: ethyl acetate ═ 1:1, product R)f0.11), the reaction was followed and purified by column chromatography (silica gel 300-: ethyl acetate 1:1) to give (S) -4-ethyl-4-hydroxy-3, 14-dioxo-3, 4,12, 14-tetrahydro-1H-pyrone [3 ', 4': 6,7] as a pale green solid]Indolyl [1,2-b ]]-9-quinolinylsulfonylfluoro [ compound 57 ]](143 mg,61％)(scheme 26)。
Light green solid, m.p.227.6-229.6 ℃,143mg, 61% yield;1H NMR(400MHz,DMSO-d6)δ 8.80(s,1H),8.48(d,J＝2.4Hz,1H),8.35(d,J＝9.2Hz,1H),8.04(dd,J＝9.2,2.4Hz,1H),7.38(s,1H),6.55(s,1H),5.43(s,2H),5.32(s,2H),1.92–1.82(m,2H),0.89(t,J＝7.2Hz,3H)；13C NMR(100MHz,DMSO-d6)δ172.4,156.6,154.1,149.9,147.4,146.8,144.7,132.1, 131.9,131.1,128.0,123.5,120.0,119.7,97.2,72.3,65.2,50.2,30.4,7.8；19F NMR(376MHz, DMSO-d6)δ+39.7(s,1F)；LC-MS(tR):1.4min；ESI-MS(m/z):447.17[MH]+(ii) a HRMS (DART, m/z) calculated value C20H16O7N2FS:447.0657[MH]+The actual value is 447.0658.
Example 27
Preparation of 4-acetamido-phenoxysulfonyl fluoride
Preparation of Scheme 274-acetamido-phenoxysulfonyl fluoride
Triethylamine (220. mu.L, 1.59mmol) was added to paracetamol [ compound 58 ] at room temperature](161mg,1.04mmol) acetonitrile (1mL), and after stirring for 10min, 1- (fluorosulfonyl) -2-3-dimethyl-1H-imidazole trifluoromethanesulfonate [ compound 4]](420mg,1.28mmol) acetonitrile (1mL) solution was added to the system in one portion and reacted for 1h under argon protection, TLC (petroleum ether: ethyl acetate ═ 1:1, product R)f0.47), the reaction was followed and purified by column chromatography (silica gel 300-: ethyl acetate 1:1) to give 4-acetamidophenoxysulfonyl fluoride [ compound 59 ] as a pale yellow solid] (238mg,98％)(scheme 27)。
Light yellow solid, m.p.150.3-152.0 ℃,238mg, 98% yield;1H NMR(400MHz,DMSO-d6)δ 10.24(s,1H),7.75(d,J＝9.2Hz,2H),7.51(d,J＝9.2Hz,2H),2.06(s,3H)；13C NMR(100 MHz,DMSO-d6)δ168.7,144.5,139.9,121.5,120.4,24.0；19F NMR(376MHz,DMSO-d6)δ +38.3(s,1F)；LC-MS(tR):1.36min；ESI-MS(m/z):234.11[MH]+(ii) a HRMS (DART, m/z) calculated value C8H9O4NFS:234.0231[MH]+The actual value is 234.0230.
Example 28
(E) Preparation of (E) -2- ((2-fluorosulfonyloxy) phenyl) azo) phenoxysulfonyl fluoride
Preparation of Scheme 28(E) -2- ((2-fluorosulfonyloxy) phenyl) azo) phenoxysulfonyl fluoride
Triethylamine (660. mu.L, 4.76mmol) was added to 2, 2-dihydroxyazobenzene [ compound 60 ] at room temperature](114mg, 0.52mmol) acetonitrile (1mL) solution, after stirring for 10min, 1- (fluorosulfonyl) -2-3-dimethyl-1H-imidazole trifluoromethanesulfonate [ compound 4]](1.267g,3.86mmol) acetonitrile (1mL) solution was added to the system in one portion and reacted under argon for 1h, TLC (petroleum ether: ethyl acetate 10:1, product R)f0.54), and column chromatography purification (silica gel 300-: ethyl acetate 10:1) to give (E) -2- ((2-fluorosulfonyloxy) phenyl) azo) phenoxysulfonyl fluoride [ compound 61 as a red solid](168mg,85％)(scheme 28)。
Red solid, m.p.116.5-118.3 ℃,168mg, 85% yield;1H NMR(400MHz,CDCl3)δ7.94 (dd,J＝8.4,1.6Hz,2H),7.68-7.64(m,2H),7.58-7.54(m,4H)；13C NMR(100MHz,CDCl3) δ148.7,143.8,133.8,129.7,122.8,118.1；19F NMR(376MHz,CDCl3)δ+39.6(s,1F)；LC-MS (tR):1.79min；ESI-MS(m/z):379.09[MH]+(ii) a HRMS (DART, m/z) calculated value C12H9O6N2F2S2: 378.9865[MH]+The actual value is 378.9862.
Example 29
Preparation of sulfur di (4, 6-dichloro-2, 1-phenyl) dioxysulfonyl fluoride
Preparation of Scheme 29 sulfur bis (4, 6-dichloro-2, 1-phenyl) dioxysulfonyl fluoride
Triethylamine (440. mu.L, 3.17mmol) was added to thiochlorophenol [ Compound 62 ] at room temperature](382mg,1.04mmol) acetonitrile (1mL) solution, after stirring for 10min, 1- (fluorosulfonyl) -2-3-dimethyl-1H-imidazole trifluoromethanesulfonate [ compound 4]](840mg,2.56mmol) acetonitrile (1mL) solution was added to the system in one portion and the mixture was stirredReaction for 1h under argon protection, TLC (petroleum ether: ethyl acetate 10:1, product R)f0.62), the reaction was followed and purified by column chromatography (silica gel 300-: ethyl acetate 10:1) to give a pale green gum thiobis (4, 6-dichloro-2, 1-phenyl) dioxosulfonyl fluoride [ compound 63 ═](507mg,94％)(scheme 29)。
Light green gum, 507mg, 94% yield;1H NMR(400MHz,CDCl3)δ7.55(d,J＝2.4Hz,2H),7.24 (d,J＝2.4Hz,2H)；13C NMR(100MHz,CDCl3)δ144.6,135.7,132.2,131.8,130.9,130.1；19F NMR(376MHz,CDCl3) δ +48.6(s, 2F); HRMS (DART, m/z) calculated value C12H4O6Cl4F2S3: 517.7887[M]+The actual value is 517.7881.
Example 30
Preparation of 8-acetyl-4-methyl-2-oxo-2H-benzopyran-7-oxysulfonyl fluoride
Preparation of Scheme 308-acetyl-4-methyl-2-oxo-2H-benzopyran-7-oxysulfonyl fluoride
Triethylamine (220. mu.L, 1.59mmol) was added to 8-acetyl-7-hydroxy-4-methylcoumarin [ compound 64 ] at room temperature](232mg,1.04mmol) acetonitrile (1mL), after stirring for 10min, 1- (fluorosulfonyl) -2-3-dimethyl-1H-imidazole trifluoromethanesulfonate [ compound 4]](420mg,1.28mmol) acetonitrile (1mL) solution was added to the system in one portion and reacted for 1h under argon protection, TLC (petroleum ether: ethyl acetate ═ 4:1, product R)f0.16), the reaction was followed and purified by column chromatography (silica gel 300-: ethyl acetate 4:1) to give 8-acetyl-4-methyl-2-oxo-2H-benzopyran-7-oxysulfonyl fluoride [ compound 65 ] as a white solid](253mg,81％)(scheme 30)。
White solid, m.p.163.8-165.2 ℃,253mg, 81% yield;1H NMR(400MHz,CDCl3)δ7.77(d, J＝8.8Hz,1H),7.37(dd,J＝8.8,1.2Hz,1H),6.39(d,J＝0.8Hz,1H),2.73(s,3H),2.48(s,3H)；13C NMR(100MHz,CDCl3)δ195.5,158.2,151.4,151.1,147.0,127.4,123.9,120.6,117.4, 116.3,32.4,19.0；19F NMR(376MHz,CDCl3)δ+40.6(s,1F)；GC-MS(tR):20.9min,EI-MS (m/z):300[M]+(ii) a HRMS (EI, m/z) calculated C12H9O6FS:300.0104[M]+The actual value is 300.0100.
Example 31
Preparation of 2-oxo-2H-6-benzopyranyl-oxysulfonyl fluoride
Preparation of Scheme 312-oxo-2H-6-benzopyranyl-oxysulfonyl fluoride
Triethylamine (220. mu.L, 1.59mmol) was added to 6-hydroxycoumarin [ Compound 66 ] at room temperature](173mg,1.04 mmol) acetonitrile (1mL), and after stirring for 10min, 1- (fluorosulfonyl) -2-3-dimethyl-1H-imidazole trifluoromethanesulfonate [ compound 4]]A solution of (448mg,1.27mmol) acetonitrile (1mL) was added to the system in one portion and reacted for 1h under argon protection, TLC (petroleum ether: ethyl acetate ═ 1:1, product Rf0.53), the reaction was followed and purified by column chromatography (silica gel 300-: ethyl acetate 1:1) to give 2-oxo-2H-6-benzopyranyl yloxysulfonyl fluoride [ compound 67 ] as a yellow solid](229mg,90％)(scheme 29)。
Yellow solid, m.p.85.3-87.9 ℃,229mg, 90% yield;1H NMR(400MHz,CDCl3)δ7.72(d,J ＝9.6Hz,1H),7.51(s,2H),7.45(d,J＝10.0Hz,1H),6.56(d,J＝10.0Hz,1H)；13C NMR(100 MHz,CDCl3)δ159.4,153.0,145.4,142.1,124.1,120.0,119.8,118.9,118.4；19F NMR(376 MHz,CDCl3)δ37.2(s,1F)；GC-MS(tR):16.8min；EI-MS(m/z):244[M]+(ii) a HRMS (EI, m/z) calculated C9H5O5FS:243.9842[M]+The actual value is 243.9839.
Example 32
Preparation of 1,3, 5-phenyl trioxanesulfonyl fluoride
Preparation of Scheme 321, 3, 5-phenyl trioxanesulfonyl fluoride
Triethylamine (660. mu.L, 4.76mmol) was added to phloroglucinol [ Compound 68 ] at room temperature](133mg,1.04mmol) acetonitrile (1mL), and after stirring for 10min, 1- (fluorosulfonyl) -2-3-dimethyl-1H-imidazole trifluoromethanesulfonate [ compound 4]](1.344g,3.81mmol) acetonitrile (1mL) solution was added to the system in one portion and reacted for 1h under argon protection, TLC (petroleum ether: ethyl acetate ═ 10:1, product R)f0.45), the reaction was followed and purified by column chromatography (silica gel 300-: ethyl acetate 30:1) to give 1,3, 5-phenyltrioxanesulfonyl fluoride [ compound 69 ] as a white solid](223 mg,57％)(scheme 32)。
White solid, m.p.95.7-97.2 ℃,223mg, 57% yield;1H NMR(400MHz,CDCl3)δ7.53(s, 3H)；13C NMR(100MHz,CDCl3)δ150.3,115.7；19F NMR(376MHz,CDCl3)δ39.6(s,3F)； GC-MS(tR):12.3min；EI-MS(m/z):372[M]+.
example 33
Preparation of methyl 2- (fluorosulfonyloxy) benzoate
Preparation of Scheme 332- (fluorosulfonyloxy) benzoic acid methyl ester
Triethylamine (220. mu.L, 1.59mmol) was added to methyl salicylate [ Compound 70 ] at room temperature](135. mu.L, 1.03 mmol) acetonitrile (1mL) solution, after stirring for 10min, 1- (fluorosulfonyl) -2-3-dimethyl-1H-imidazole trifluoromethanesulfonate [ Compound 4]]A solution of (448mg,1.27mmol) acetonitrile (1mL) was added to the system in one portion and reacted for 1h under argon protection, TLC (petroleum ether: ethyl acetate 10:1, product Rf0.38), the reaction was followed and purified by column chromatography (silica gel 300-: ethyl acetate ═ 30:1, 20:1) to give methyl 2- (fluorosulfonyloxy) benzoate [ compound 71] as a colorless liquid](196mg,81％)(scheme 33)。
Colorless liquid, 196mg, 81% yield;1H NMR(400MHz,CDCl3)δ8.12(d,J＝8.0Hz,1H),7.67 (t,J＝8.0Hz,1H),7.52(t,J＝8.0Hz,1H),7.42(d,J＝8.0Hz,1H),3.98(s,3H)；13C NMR(100 MHz,CDCl3)δ163.8,148.5,134.5,132.9,128.9,123.8,122.5,52.7；19F NMR(376MHz, CDCl3)δ41.2(s,1F)；GC-MS(tR):11.8min；EI-MS(m/z):234[M]+(ii) a HRMS (EI, m/z) calculated C8H7O5FS:233.9998[M]+The actual value is 233.9995.
Example 34
Preparation of 5, 7-dichloro-2-methyl-quinoline-8-oxysulfonyl fluoride
Preparation of Scheme 345, 7-dichloro-2-methyl-quinoline-8-oxysulfonyl fluoride
Triethylamine (220. mu.L, 1.59mmol) was added to 5, 7-dichloro-8-hydroxyquinaldine [ compound 72] at room temperature](243 mg,1.04mmol) acetonitrile (1mL), after stirring for 10min, 1- (fluorosulfonyl) -2-3-dimethyl-1H-imidazole trifluoromethanesulfonate [ compound 4]](420mg,1.28mmol) acetonitrile (1mL) solution was added to the system in one portion and reacted for 1h under argon protection, TLC (petroleum ether: ethyl acetate ═ 10:1, product R)f0.64), and purified by column chromatography (silica gel 300-: ethyl acetate 10:1) to give 5, 7-dichloro-2-methyl-quinoline-8-oxysulfonyl fluoride [ compound 73] as a pale green solid](314mg,97％)(scheme 34)。
Light green solid, m.p.64.6-66.2 ℃,314mg, 97% yield;1H NMR(400MHz,CDCl3)δ8.41(d, J＝8.8Hz,1H),7.65(s,1H),7.49(d,J＝8.8Hz,1H),2.81(s,3H)；13C NMR(100MHz,CDCl3) δ162.8,141.4,133.2,131.9,127.6,126.4,124.7,124.4,25.6；19F NMR(376MHz,CDCl3)δ +47.2(s,1F)；LC-MS(tR):1.8min；ESI-MS(m/z):309.92[MH]+(ii) a HRMS (DART, m/z) calculated value C10H7O3NCl2FS:309.9502[MH]+The actual value is 309.9502.
Example 35
Preparation of 5-nitro-quinoline-8-oxysulfonyl fluoride
Preparation of Scheme 355-nitro-quinoline-8-oxysulfonyl fluoride
Triethylamine (220. mu.L, 1.59mmol) was added to 5-nitro-8-hydroxyquinoline [ Compound 74] at room temperature](207mg, 1.04mmol) acetonitrile (1mL), and after stirring for 10min, 1- (fluorosulfonyl) -2-3-dimethyl-1H-imidazole trifluoromethanesulfonate [ compound 4]](420mg,1.28mmol) acetonitrile (1mL) solution was added to the system in one portion and reacted for 1h under argon protection, TLC (petroleum ether: ethyl acetate ═ 1:1, product R)f0.70), the reaction was followed and purified by column chromatography (silica gel 300-: ethyl acetate 1:1) to give 5-nitro-quinoline-8-oxysulfonyl fluoride [ compound 75] as a pale green solid](281mg,99％)(scheme 35)。
Light green solid, m.p.86.9-87.9 ℃,281mg, 99% yield;1H NMR(400MHz,CDCl3)δ9.18 (dd,J＝4.2,1.4Hz,1H),9.06(dd,J＝8.9,1.4Hz,1H),8.46(d,J＝8.4Hz,1H),7.87(d,J＝8.4 Hz,1H),7.81(dd,J＝8.9,4.2Hz,1H)；13CNMR(100MHz,CDCl3)δ152.9,149.5,145.0, 140.6,132.4,125.5,124.5,123.1,120.0；19F NMR(376MHz,CDCl3)δ+42.1(s,1F)；LC-MS (tR):1.5min；ESI-MS(m/z):273.01[MH]+(ii) a HRMS (DART, m/z) calculated value C9H6O5N2FS: 272.9976[MH]+The actual value is 272.9975.
Example 36
Preparation of 4-allyl-2-methoxy-phenoxy-sulfonyl fluoride
Preparation of Scheme 364-allyl-2-methoxyphenoxysulfonyl fluoride
Triethylamine (220. mu.L, 1.59mmol) was added to eugenol [ compound 76] at room temperature](163. mu.L, 1.04mmol) acetonitrile (1mL) solution, stirred for 10min1- (fluorosulfonyl) -2-3-dimethyl-1H-imidazole trifluoromethanesulfonate [ compound 4]]A solution of (448mg,1.27mmol) acetonitrile (1mL) was added to the system in one portion and reacted for 1h under argon protection, TLC (petroleum ether: ethyl acetate 10:1, product Rf0.66), the reaction was followed and purified by column chromatography (silica gel 300-: ethyl acetate 30:1) to give 4-allyl-2-methoxyphenoxysulfonyl fluoride [ compound 77 as a colorless liquid](247mg,96％)(scheme 36)。
Colorless liquid, 247mg, 96% yield;1H NMR(400MHz,CDCl3)δ7.22(d,J＝8.0Hz,1H),6.86 (s,1H),6.81(d,J＝8.0Hz,1H),5.99-5.89(m,1H),5.14(s,1H),5.11(d,J＝8.0Hz,1H),3.90 (s,3H),3.40(d,J＝8.0Hz,2H)；13C NMR(100MHz,CDCl3)δ151.0,142.4,137.3,136.3, 122.1,120.8,116.8,113.7,56.1,40.0；19F NMR(376MHz,CDCl3)δ38.9(s,1F)；GC-MS(tR): 13.7min；EI-MS(m/z):246[M]+.
example 37
Preparation of 4-formyl-2-methoxy-phenoxy-sulfonyl fluoride
Preparation of Scheme 374-formyl-2-methoxyphenoxysulfonyl fluoride
Triethylamine (220. mu.L, 1.59mmol) was added to vanillin [ Compound 78] at room temperature](162mg,1.04mmol) acetonitrile (1mL), and after stirring for 10min, 1- (fluorosulfonyl) -2-3-dimethyl-1H-imidazole trifluoromethanesulfonate [ compound 4]]A solution of (448mg,1.27mmol) acetonitrile (1mL) was added to the system in one portion and reacted for 1h under argon protection, TLC (petroleum ether: ethyl acetate 10:1, product Rf0.26) and purified by column chromatography (silica gel 300-: ethyl acetate ═ 20:1,10:1) to give 4-formyl-2-methoxyphenoxysulfonyl fluoride [ compound 79] as a pale yellow solid](230mg,94％)(scheme 37)。
Pale yellow solid, m.p.50.8-51.8 ℃,230mg, 94% yield;1H NMR(400MHz,CDCl3)δ10.00 (s,1H),7.58(s,1H),7.52(t,J＝10.0Hz,2H),4.01(s,3H)；13C NMR(100MHz,CDCl3)δ190.4, 152.0,142.7,137.1,123.8,123.1,112.2,56.5；19F NMR(376MHz,CDCl3)δ40.5(s,1F)；GC- MS(tR):13.4min；EI-MS(m/z):234[M]+.
example 38
Preparation of 4-fluorosulfonyloxybenzoic acid methyl ester
Preparation of Scheme 384-fluorosulfonyloxymethyl benzoate
Triethylamine (220. mu.L, 1.59mmol) was added to methyl 4-hydroxybenzoate [ Compound 80] at room temperature](160mg, 1.04mmol) acetonitrile (1mL), after stirring for 10min, 1- (fluorosulfonyl) -2-3-dimethyl-1H-imidazole trifluoromethanesulfonate [ compound 4]]A solution of (448mg,1.27mmol) acetonitrile (1mL) was added to the system in one portion and reacted for 1h under argon protection, TLC (petroleum ether: ethyl acetate 10:1, product Rf0.43), the reaction was followed and purified by column chromatography (silica gel 300-: ethyl acetate 30:1) to give colorless liquid methyl 4-fluorosulfonyloxybenzoate [ compound 81]](201mg,82％)(scheme 38)。
Colorless liquid, 201mg, 82% yield;1H NMR(400MHz,CDCl3)δ8.17(d,J＝8.0Hz,2H),7.42 (d,J＝8.0Hz,2H),3.95(s,3H)；13C NMR(100MHz,CDCl3)δ165.4,152.9,132.1,130.7, 121.0,52.6；19F NMR(376MHz,CDCl3)δ38.2(s,1F)；GC-MS(tR):12.2min；EI-MS(m/z): 234[M]+(ii) a HRMS (EI, m/z) calculated C8H7O5FS:233.9998[M]+The actual value is 233.9997.
Example 39
Preparation of 2-ethyl-6-methylpyridine-3-oxysulfonyl fluoride
Preparation of Scheme 392-ethyl-6-methylpyridine-3-oxysulfonyl fluoride
Triethylamine (220. mu.L, 1.59mmol) was added to 2-ethyl-6-methyl-3-hydroxy-pyridine [ compound 82] at room temperature](146mg,1.04mmol) acetonitrile (1mL), after stirring for 10min, 1- (fluorosulfonyl) -2-3-dimethyl-1H-imidazole trifluoromethanesulfonate [ compound 4]]A solution of (448mg,1.27mmol) acetonitrile (1mL) was added to the system in one portion and reacted for 1h under argon protection, TLC (petroleum ether: ethyl acetate 10:1, product Rf0.59), the reaction was followed and purified by column chromatography (silica gel 300-: ethyl acetate ═ 30:1) to give 2-ethyl-6-methylpyridine-3-oxysulfonyl fluoride [ compound 83] as a colorless liquid](154mg,67％)(scheme 39)。
Colorless liquid, 154mg, 67% yield;1H NMR(400MHz,CDCl3)δ7.51(d,J＝8.0Hz,1H),7.09 (d,J＝8.0Hz,1H),2.88(q,J＝14.0Hz,2H),2.57(s,3H),1.31(t,J＝8.0Hz,3H)；13C NMR (100MHz,CDCl3)δ158.6,154.9,143.6,128.7,122.1,25.6,24.1,12.7；19F NMR(376MHz, CDCl3)δ39.1(s)；GC-MS(tR):9.3min；EI-MS(m/z):219[M]+(ii) a HRMS (EI, m/z) calculated C8H10NO3FS:219.0365[M]+The actual value is 219.0371.
Example 40
Preparation of 2-isopropyl-5-methylphenoxysulfonyl fluoride
Preparation of Scheme 402-isopropyl-5-methylphenoxysulfonyl fluoride
Triethylamine (220. mu.L, 1.59mmol) was added to thymol [ compound 84] at room temperature](158mg,1.04mmol) acetonitrile (1mL) solution, after stirring for 10min, 1- (fluorosulfonyl) -2-3-dimethyl-1H-imidazole trifluoromethanesulfonate [ compound 4]]A solution of (448mg,1.27mmol) acetonitrile (1mL) was added to the system in one portion and reacted for 1h under argon protection, TLC (petroleum ether: ethyl acetate 10:1, product Rf0.76) and purified by column chromatography (silica gel 300-: ethyl acetate 30:1) to give 2-isopropyl-5-methylphenoxysulfonyl fluoride [ compound 85] as a colorless liquid](182mg,75％)(scheme 40)。
Colorless liquid, 182mg, 75% yield;1H NMR(400MHz,CDCl3)δ7.28(d,J＝8.0Hz,1H),7.17 (d,J＝8.0Hz,1H),7.11(s,1H),3.25(sept,J＝6.6Hz,1H),2.36(s,3H),1.24(d,J＝8.0Hz,6H)；13C NMR(100MHz,CDCl3)δ147.9,137.9,137.6,129.8,127.7,121.1,26.8,23.2,20.8；19F NMR(376MHz,CDCl3)δ38.9(s,1F)；GC-MS(tR):10.7min；EI-MS(m/z):232[M]+.
EXAMPLE 41
Preparation of 3-nitrophenoxysulfonyl fluorides
Preparation of Scheme 413-nitrophenoxysulfonyl fluoride
Triethylamine (220. mu.L, 1.59mmol) was added to m-nitrophenol [ Compound 86 ] at room temperature](148mg,1.04mmol) acetonitrile (1mL), and after stirring for 10min, 1- (fluorosulfonyl) -2-3-dimethyl-1H-imidazole trifluoromethanesulfonate [ Compound 4]](420mg,1.28mmol) acetonitrile (1mL) solution was added to the system in one portion and reacted for 1h under argon protection, TLC (petroleum ether: ethyl acetate ═ 10:1, product R)f0.42), and purified by column chromatography (silica gel 300-: ethyl acetate 10:1) to obtain 3-nitrophenoxysulfonyl fluoride [ compound 87] as a green liquid](196mg, 85％)(scheme 41)。
Green liquid, 196mg, 85% yield;1H NMR(400MHz,CDCl3)δ8.36-8.31(m,1H),8.25(s, 1H),7.76-7.73(m,2H)；13C NMR(100MHz,CDCl3)δ149.8,149.2,131.6,127.3,123.8,117.1；19F NMR(376MHz,CDCl3)δ+38.6(s,1F)；GC-MS(tR):11.6min,EI-MS(m/z):221[M]+(ii) a HRMS (EI, m/z) calculated C6H4NO5FS:220.9794[M]+The actual value is 220.9800.
Example 42
Preparation of 1-naphthyl oxysulfonyl fluoride
Preparation of Scheme 421-naphthyl oxysulfonyl fluoride
Triethylamine (220. mu.L, 1.59mmol) was added to 1-naphthol [ Compound 88] at room temperature](150mg,1.04mmol) acetonitrile (1mL), and after stirring for 10min, 1- (fluorosulfonyl) -2-3-dimethyl-1H-imidazole trifluoromethanesulfonate [ compound 4]](421mg,1.28mmol) acetonitrile (1mL) solution was added to the system in one portion and reacted for 1h under argon protection, TLC (petroleum ether: ethyl acetate ═ 10:1, product R)f0.64), and purified by column chromatography (silica gel 300-: ethyl acetate 10:1) to give 1-naphthyloxysulfonyl fluoride [ compound 89] as a pale green liquid](178mg,76％) (scheme 42)。
Pale green liquid, 178mg, 76% yield;1H NMR(400MHz,CDCl3)δ8.10(d,J＝8.0Hz,1H), 7.92(dd,J＝12.4,7.6Hz,2H),7.69-7.60(m,2H),7.56-7.49(m,2H)；13C NMR(100MHz, CDCl3)δ146.3,135.1,128.9,128.2,128.0,127.6,125.9,125.2,120.7,117.7；19F NMR(376 MHz,CDCl3)δ+38.5(s,1F)；GC-MS(tR):13.7min,EI-MS(m/z):226[M]+.
example 43
Preparation of 1-naphthyl [2,3-d ] [1,3,2] dioxa-2, 2-dioxythiophene
Preparation of Scheme 431-naphthyl [2,3-d ] [1,3,2] dioxa-2, 2-dioxythiophene
Triethylamine (440. mu.L, 3.17mmol) was added to 2, 3-dihydroxynaphthalene [ Compound 90] at room temperature](169mg,1.04 mmol) acetonitrile (1mL), and after stirring for 10min, 1- (fluorosulfonyl) -2-3-dimethyl-1H-imidazole trifluoromethanesulfonate [ compound 4]](421g,1.28mmol) acetonitrile (1mL) solution was added to the system in one portion and reacted for 1h under argon protection, TLC (petroleum ether: ethyl acetate ═ 10:1, product Rf0.56), the reaction was followed and purified by column chromatography (silica gel 300-: ethyl acetate 10:1) to give 1-naphthyl [2, 3-d) as a white solid][1,3,2]Dioxa-2, 2-dioxythiophene [ compound 91-1 ]](132mg,57％)(scheme 43)。
White solid, m.p.112.8-121.1 ℃,132mg, 57% yield;1H NMR(400MHz,CDCl3)δ7.83 (dd,J＝5.4,2.4Hz,2H),7.57-7.54(m,4H)；13C NMR(100MHz,CDCl3)δ141.5,130.4,128.1, 127.1,108.7；19F NMR(376MHz,CDCl3)δ+40.0(s,2F)；GC-MS(tR):16.9min,EI-MS(m/z): 222[M]+(ii) a HRMS (EI, m/z) calculated C10H6O4S:221.9987[M]+The actual value is 221.9993.
Example 44
Preparation of benzo [ d ] [1,3,2] dioxa-2, 2-dioxythiophene
Preparation of Scheme 44 benzo [ d ] [1,3,2] dioxa-2, 2-dioxythiophene
Triethylamine (220. mu.L, 1.59mmol) was added to catechol [ Compound 92] at room temperature](117mg,1.05mmol) acetonitrile (1mL) solution, after stirring for 10min, 1- (fluorosulfonyl) -2-3-dimethyl-1H-imidazole trifluoromethanesulfonate [ compound 4]]A solution of (448mg,1.27mmol) acetonitrile (1mL) was added to the system in one portion and reacted for 1h under argon protection, TLC (petroleum ether: ethyl acetate 10:1, product Rf0.47), the reaction was followed and purified by column chromatography (silica gel 300-: ethyl acetate 10:1) to give benzo [ d ] a white solid][1,3,2]Dioxa-2, 2-dioxythiophene [ compound 93]](74mg,40％)(scheme 44)。
White solid, m.p.33.4-35.4 ℃,74mg, 40% yield;1H NMR(400MHz,CDCl3)δ7.22(s, 4H)；13C NMR(100MHz,CDCl3)δ142.7,125.5,111.9；19F NMR(376MHz,CDCl3)no signal； GC-MS(tR):9.0min；EI-MS(m/z):172[M]+.
example 45
Preparation of 2, 6-diisopropyl phenoxy sulfonyl fluoride
Preparation of Scheme 452, 6-diisopropyl phenoxy sulfonyl fluoride
Triethylamine (220. mu.L, 1.59mmol) was added to propofol [ Compound 94] at room temperature](190mg,1.04mmol) acetonitrile (1mL), after stirring for 10min, 1- (fluorosulfonyl) -2-3-dimethyl-1H-imidazole trifluoromethanesulfonate [ compound 4]](420mg,1.28mmol) acetonitrile (1mL) solution was added to the system in one portion and reacted for 1h under argon protection, TLC (petroleum ether: ethyl acetate ═ 10:1, product R)f0.74), the reaction was followed and purified by column chromatography (silica gel 300-: ethyl acetate ═ 20:1) to give 2, 6-diisopropylbenzenesulfonyl fluoride [ compound 95] as a colorless liquid](193 mg,71％)(scheme 45)。
Colorless liquid, 193mg, 71% yield;1H NMR(400MHz,CDCl3)δ7.35-7.31(m,1H),7.23(d, J＝7.6Hz,2H),3.30(sept,J＝6.8Hz,2H),1.26(d,J＝6.8Hz,12H)；13C NMR(100MHz, CDCl3)δ146.4,141.4,129.0,125.4,27.4(d,J＝1.5Hz),23.6；19F NMR(376MHz,CDCl3)δ +41.3(s,1F)；GC-MS(tR):11.8min,EI-MS(m/z):260[M]+(ii) a HRMS (EI, m/z) calculated C12H17O3FS:260.0882[M]+The actual value is 260.0886.
Example 46
Preparation of 1, 3-dioxoisoindole-2-sulfonyl fluoride
Preparation of Scheme 461, 3-dioxoisoindole-2-sulfonyl fluoride
Phthalimide potassium salt [ compound 96] (93mg,0.5mmol) was dissolved in acetonitrile (2mL) at room temperature, 1- (fluorosulfonyl) -2, 3-dimethyl-1H-imidazole trifluoromethanesulfonate [ compound 4] (164mg,0.5mmol) was added and reacted for 2 hours, and the formation of a part of 1, 3-dioxoisoindole-2-sulfonyl fluoride [ compound 97] was monitored by GC-MS, and the disappearance of the signal was monitored after extraction (Scheme 46).
GC-MS(tR):9.8min；EI-MS(m/z):229[M]+.
Example 47
Preparation of 3-oxobenzo [ d ] isothiazole-2 (3H) -sulfonyl fluoride-1, 1-dioxide
Scheme 473-oxobenzo [ d ] isothiazole-2 (3H) -sulfonyl fluoride-1, 1-dioxide
Saccharin [ compound 98] (93mg,0.5mmol) was dissolved in acetonitrile (2mL) at room temperature, 1- (fluorosulfonyl) -2, 3-dimethyl-1H-imidazole trifluoromethanesulfonate [ compound 4] (164mg,0.5mmol) was added and reacted for 2 hours, and the partial product 3-oxobenzo [ d ] isothiazole-2 (3H) -sulfonyl fluoride-1, 1-dioxide [ compound 99] was detected by GC-MS, and the disappearance of the signal was monitored after extraction (Scheme 47).
GC-MS(tR):14.3min；EI-MS(m/z):265[M]+.
Example 48
Preparation of 4-benzylpiperazine-1-sulfonyl fluoride
Preparation of Scheme 484-benzylpiperazine-1-sulfonyl fluoride
Dissolving 1-benzylpiperazine [ compound 100] (176mg,1mmol) in acetonitrile (3mL) at room temperature, adding 1- (fluorosulfonyl) -2, 3-dimethyl-1H-imidazole trifluoromethanesulfonate [ compound 4] (328mg,1mmol), reacting for 2H, detecting the reaction completion by GC-MS, adding water (30mL) to the reaction solution, extracting with ethyl acetate (20mL × 3), combining the organic phases, washing with water (20mL) and saturated saline (20mL), drying over anhydrous sodium sulfate, filtering with filter paper, concentrating the filtrate by a rotary evaporator, and pumping off the solvent by an oil pump to obtain 4-benzylpiperazine-1-sulfonyl fluoride [ compound 101] (219mg, 85%) (Scheme 48).
Yellow oil, 219mg, 85% yield;1H NMR(400MHz,CDCl3)δ7.32(m,5H),3.56(s,2H), 3.47(s,4H),2.57(s,4H)；13C NMR(100MHz,CDCl3)δ137.3,129.1,128.6,127.6,62.6,51.6, 47.2；19F NMR(376MHz,CDCl3)δ38.2(s,1F)；GC-MS(tR):10.4min；EI-MS(m/z):258[M]+(ii) a HRMS (EI, m/z) calculated C11H15N2O2FS:258.0838[M]+The actual value is 258.0842.
Example 49
Preparation of 2- (m-tolyl) pyrrolidine-1-sulfonyl fluoride
Preparation of Scheme 492- (3-tolyl) -pyrrolidine-1-sulfonyl fluoride
2- (3-tolyl) -pyrrolidine [ compound 102] (161mg,1mmol) was dissolved in acetonitrile (3mL) at room temperature, adding 1- (fluorosulfonyl) -2, 3-dimethyl-1H-imidazole trifluoromethanesulfonate [ compound 4] (328mg,1mmol), reacting for 2H, detecting by GC-MS that the reaction is finished, adding water (30mL) to the reaction solution, extraction with ethyl acetate (20 mL. times.3), combination of the organic phases, washing with water (20mL), saturated brine (20mL), drying over anhydrous sodium sulfate, filtration through a filter paper, concentration of the filtrate by rotary evaporator, and oil pump-off of the solvent gave 2- (3-tolyl) -pyrrolidine-1-sulfonylfluoride [ compound 103] (198mg, 81%) (Scheme 49) as a yellow oil.
Yellow oil, 198mg, 81% yield;1H NMR(400MHz,CDCl3)δ7.28-7.08(m,4H),4.98(m, 1H),3.75(m,2H),2.44(m,1H),2.37(s,3H),2.05(m,3H)；13C NMR(100MHz,CDCl3)δ 140.9,138.3,128.5,126.5,122.9,65.0,50.9,36.0,24.2,21.5；19F NMR(376MHz,CDCl3)δ 39.1(s,1F)；GC-MS(tR):9.8min；EI-MS(m/z):243[M]+(ii) a HRMS (EI, m/z) calculated C11H14NO2FS:243.0729[M]+The actual value is 243.0735.
Example 50
Preparation of N-methylanilino sulfonyl fluoride
Preparation of Scheme 50N-methylanilino sulfonyl fluoride
Dissolving N-methylaniline [ compound 104] (1.07g,10mmol) in acetonitrile (10mL), adding 1- (fluorosulfonyl) -2, 3-dimethyl-1H-imidazole trifluoromethanesulfonate [ compound 4] (3.28g,10mmol) under ice bath, removing ice bath after completion of the reaction, reacting at room temperature for 2 hours, detecting completion of the reaction by GC-MS, adding water (50mL) to the reaction solution, extracting with ethyl acetate (30 mL. times.3), combining the organic phases, washing with water (30mL), washing with saturated saline (30mL), drying with anhydrous sodium sulfate, filtering with filter paper, concentrating the filtrate by a rotary evaporator, and pumping off the solvent by an oil pump to obtain a yellow oily N-methylaniline fluorosulfonyl [ compound 105] (1.56g, 83%) (Scheme 50).
Yellow oil, 1.56g, 83% yield;1H NMR(400MHz,CDCl3)δ7.43(m,5H),3.44(d,J＝2.4 Hz,3H)；13C NMR(100MHz,CDCl3)δ139.9(d,J＝2.8Hz),139.9,129.1,126.7(d,J＝2.1 Hz),40.7(d,J＝1.5Hz)；19F NMR(376MHz,CDCl3)δ41.8(s,1F)；GC-MS(tR):6.9min；EI- MS(m/z):189[M]+(ii) a HRMS (EI, m/z) calculated C7H8NO2FS:189.0260[M]+The actual value is 189.0257.
Example 51
Preparation of 2- (p-tolyl) pyrrolidine-1-sulfonyl fluoride
Preparation of Scheme 512- (4-tolyl) -pyrrolidine-1-sulfonyl fluoride
2- (4-tolyl) -pyrrolidine [ compound 106] (161mg,1mmol) was dissolved in acetonitrile (3mL) at room temperature, 1- (fluorosulfonyl) -2, 3-dimethyl-1H-imidazole trifluoromethanesulfonate [ compound 4] (328mg,1mmol) was added thereto, and the mixture was reacted for 2 hours, after completion of the reaction, water (30mL) was added to the reaction mixture, extracted with ethyl acetate (20 mL. times.3), the organic phases were combined, washed with water (20mL) and saturated brine (20mL), dried over anhydrous sodium sulfate, filtered through filter paper, and the filtrate was concentrated by rotary evaporator, and the solvent was removed by oil pump to give 2- (4-tolyl) -pyrrolidine-1-sulfonyl fluoride [ compound 107] (181mg, 74%) (Scheme 51) as a pale yellow solid.
Pale yellow solid, m.p.53-57 ℃,181mg, 74% yield;1H NMR(400MHz,CDCl3)δ7.17(m, 4H),4.97(m,1H),3.74(m,2H),2.44(m,1H),2.34(s,3H),2.03(m,3H)；13C NMR(100MHz, CDCl3)δ138.0,137.5,129.3,125.8,64.9,50.8,36.0,24.2,21.1；19F NMR(376MHz,CDCl3) δ39.3(s,1F)；GC-MS(tR):9.9min；EI-MS(m/z):243[M]+(ii) a HRMS (EI, m/z) calculated C11H14NO2FS:243.0729[M]+The actual value is 243.0731.
Example 52
Preparation of N-isopropylbenzylamine sulfonyl fluoride
Preparation of Scheme 52N-benzyl isopropylamine sulfonyl fluoride
N-benzyl isopropylamine [ compound 108] (149mg,1mmol) was dissolved in acetonitrile (3mL) at room temperature, 1- (fluorosulfonyl) -2, 3-dimethyl-1H-imidazole trifluoromethanesulfonate [ compound 4] (328mg,1mmol) was added thereto, the reaction was carried out for 2 hours, GC-MS detection of the completion of the reaction was carried out, water (30mL) was added to the reaction solution, ethyl acetate (20mL × 3) was extracted, the organic phases were combined and washed with water (20mL) and saturated brine (20mL), dried over anhydrous sodium sulfate, filter paper was filtered, the filtrate was concentrated by a rotary evaporator, and the solvent was pumped off by an oil pump to obtain N-benzyl isopropylamine sulfonylfluoride [ compound 109] (176mg, 76%) as a yellow oily substance (Scheme 52).
Yellow oil, 176mg, 76% yield;1H NMR(400MHz,CDCl3)δ7.34(m,5H),4.49(s,2H), 4.07(sept,J＝6.8Hz,1H),1.23(d,J＝6.8Hz,6H)；13C NMR(100MHz,CDCl3)δ136.3(d,J ＝2.2Hz),128.8,128.1,127.6,53.5(d,J＝2.4Hz),49.7(d,J＝1.9Hz),20.5(d,J＝2.1Hz)；19F NMR(376MHz,CDCl3)δ50.6(s,1F)；GC-MS(tR):8.4min；EI-MS(m/z):231[M]+(ii) a HRMS (EI, m/z) calculated C10H14NO2FS:231.0729[M]+The actual value is 231.0740.
Example 53
Preparation of N-ethylbenzylamine sulfonyl fluoride
Preparation of Scheme 53N-ethylbenzylamine sulfonyl fluoride
N-ethylbenzylamine [ compound 110] (135mg,1mmol) was dissolved in acetonitrile (3mL) at room temperature, 1- (fluorosulfonyl) -2, 3-dimethyl-1H-imidazole trifluoromethanesulfonate [ compound 4] (328mg,1mmol) was added thereto, the reaction was carried out for 2 hours, GC-MS detection of the completion of the reaction was carried out, water (30mL) was added to the reaction solution, ethyl acetate (20mL × 3) was extracted, the organic phases were combined and washed with water (20mL) and saturated saline (20mL), dried over anhydrous sodium sulfate, filter paper was filtered, the filtrate was concentrated by a rotary evaporator, and the solvent was pumped off by an oil pump to obtain N-ethylbenzylamine sulfonyl fluoride [ compound 111] (177mg, 82%) (Scheme 53) as a yellow oily substance.
Yellow oil, 177mg, 82% yield;1H NMR(400MHz,CDCl3,TMS)δ7.37(m,5H),4.51(s, 2H),3.34(dq,J＝2.4Hz,J＝7.2Hz,2H),1.19(t,J＝7.2Hz,3H)；13C NMR(100MHz,CDCl3) δ134.3(d,J＝2.1Hz),129.0,128.6,128.4,51.7(d,J＝1.8Hz),43.5(d,J＝2.3Hz),12.2；19F NMR(376MHz,CDCl3)δ49.8(s,1F)；GC-MS(tR):7.9min；EI-MS(m/z):217[M]+(ii) a HRMS (EI, m/z) calculated C9H12NO2FS:217.0537[M]+The actual value is 217.0576.
Example 54
Preparation of 4-benzylpiperidine-1-sulfonyl fluoride
Preparation of Scheme 544-benzylpiperidine-1-sulfonyl fluoride
4-benzylpiperidine [ compound 112] (175mg,1mmol) was dissolved in acetonitrile (3mL) at room temperature, 1- (fluorosulfonyl) -2, 3-dimethyl-1H-imidazole trifluoromethanesulfonate [ compound 4] (328mg,1mmol) was added thereto, the reaction was carried out for 2 hours, GC-MS showed completion of the reaction, water (30mL) was added to the reaction solution, ethyl acetate (20 mL. times.3) was extracted, the organic phases were combined and washed with water (20mL) and saturated brine (20mL), dried over anhydrous sodium sulfate, filtered through filter paper, the filtrate was concentrated by a rotary evaporator, and the solvent was pumped off by an oil pump to obtain 4-benzylpiperidine-1-sulfonylfluoride [ compound 113] (190mg, 74%) (Scheme 39) as a pale yellow solid.
Pale yellow solid, m.p.54-58 ℃,190mg, 74% yield;1H NMR(400MHz,CDCl3)δ7.32-7.13 (m,5H),3.91(d,J＝12.8Hz,2H),2.93(t,J＝12.8Hz,2H),2.58(d,J＝6.8Hz,2H),1.76(d,J＝14Hz,2H),1.68(m,1H),1.38(dq,J＝4Hz,J＝11.6Hz,2H)；13C NMR(100MHz,CDCl3) δ139.4,129.1,128.4,126.3,47.5,42.5,37.0,30.7；19F NMR(376MHz,CDCl3)δ39.6(s,1F)； GC-MS(tR):10.8min；EI-MS(m/z):257[M]+(ii) a HRMS (EI, m/z) calculated C12H16NO2FS: 257.0886[M]+The actual value is 257.0887.
Example 55
Preparation of 4-phenylpiperidine-1-sulfonyl fluoride
Preparation of Scheme 554-phenylpiperidine-1-sulfonyl fluoride
4-phenylpiperidine hydrochloride [ compound 114] (197mg,1mmol) was dissolved in acetonitrile (10mL) at room temperature, sodium hydrogencarbonate (168mg,2mmol) was added thereto and the reaction was carried out for 2 hours, the solid was removed by filtration, and 1- (fluorosulfonyl) -2, 3-dimethyl-1H-imidazole trifluoromethanesulfonate [ compound 4] (328mg,1mmol) was added thereto to react for 2 hours, after the reaction was completed, GC-MS detected that water (30mL) was added to the reaction mixture, ethyl acetate (20 mL. times.3) was extracted, the organic phases were combined, washed with water (20mL) and saturated brine (20mL), dried over anhydrous sodium sulfate, filtered through filter paper, and the filtrate was concentrated by a rotary evaporator, and the solvent was pumped off by an oil pump to give 4-phenylpiperidine-1-sulfonyl fluoride [ compound 116] (168mg, 70%) (Scheme 55) as a white solid.
White solid, m.p.83-84 deg.C, 168mg, 69%Yield;1H NMR(400MHz,CDCl3)δ7.36–7.20 (m,5H),4.06(d,J＝12.8Hz,2H),3.12(t,J＝12.4Hz,2H),2.68(t,J＝12.4Hz,1H),1.97(d, J＝12.8Hz,2H),1.87(dq,J＝4Hz,J＝12.8Hz,2H)；13C NMR(100MHz,CDCl3)δ144.2, 128.8,126.9,126.7,47.9,41.4,32.0；19F NMR(376MHz,CDCl3)δ39.8(s,1F)；GC-MS(tR): 10.1min；EI-MS(m/z):243[M]+(ii) a HRMS (EI, m/z) calculated C11H14NO2FS:243.0729[M]+The actual value is 243.0733.
Example 56
Preparation of 3- (benzyloxy) azetidine-1-sulfonyl fluoride
Preparation of Scheme 563- (benzyloxy) azetidine-1-sulfonyl fluoride
3- (benzyloxy) azetidine hydrochloride [ compound 117] (199mg,1mmol) was dissolved in acetonitrile (10mL) at room temperature, sodium hydrogencarbonate (168mg,2mmol) was added and reacted for 2 hours, the solid was removed by filtration, 1- (fluorosulfonyl) -2, 3-dimethyl-1H-imidazole trifluoromethanesulfonate [ compound 4] (328mg,1mmol) was added and reacted for 2 hours, GC-MS detected that the reaction was completed, water (30mL) was added to the reaction solution, ethyl acetate (20 mL. times.3) was extracted, the organic phases were combined and washed with water (20mL), saturated brine (20mL), dried over anhydrous sodium sulfate, filtered through filter paper, the filtrate was concentrated by rotary evaporator, the solvent was pumped by an oil pump to give 3- (benzyloxy) azetidine-1-sulfonylfluoride [ compound 119] (232mg, 95%) (Scheme 56).
Yellow oil, 232mg, 95% yield;1H NMR(400MHz,CDCl3)δ7.35(m,5H),4.49(s,2H), 4.41(quin,J＝6Hz,1H),4.20(t,J＝7.6Hz,2H),4.07(m,2H)；13C NMR(100MHz,CDCl3) δ136.5,128.7,128.5,128.1,71.8,66.2,60.3；19F NMR(376MHz,CDCl3)δ29.0(s,1F)；GC- MS(tR):10.0min；EI-MS(m/z):245[M]+(ii) a HRMS (EI, m/z) calculated C10H12NO3FS:245.0522 [M]+The actual value is 245.0530.
Example 57
Preparation of 3- [3- (trifluoromethyl) phenoxy ] -azetidine-1-sulfonyl fluoride
Preparation of Scheme 573- [3- (trifluoromethyl) phenoxy ] -azetidine-1-sulfonyl fluoride
Dissolving 3- [3- (trifluoromethyl) phenoxy ] -azetidine hydrochloride [ compound 120] (253mg,1mmol) in acetonitrile (10mL) at room temperature, adding sodium bicarbonate (168mg,2mmol), reacting for 2 hours, filtering to remove solids, adding 1- (fluorosulfonyl) -2, 3-dimethyl-1H-imidazole trifluoromethanesulfonate [ compound 4] (328mg,1mmol), reacting for 2 hours, detecting completion of the reaction by GC-MS, adding water (30mL) to the reaction solution, extracting with ethyl acetate (20 mL. times.3), combining the organic phases, washing with water (20mL) and saturated saline (20mL), drying with anhydrous sodium sulfate, filtering, concentrating the filtrate by a rotary evaporator, pumping off the solvent to obtain a yellow oily substance, namely 3- [3- (trifluoromethyl) phenoxy ] -azetidine-1-sulfonyl fluoride [ compound 112] ] (252mg, 84%) (Scheme 58).
Yellow oil, 252mg, 84% yield;1H NMR(400MHz,CDCl3)δ7.44(t,J＝8Hz,1H),7.31 (d,J＝7.6Hz,1H),6.98(s,1H),6.93(d,J＝8.4Hz,1H),5.06(quin,J＝5.6Hz,1H),4.55(t,J ＝8Hz,2H),4.29(m,2H)；13C NMR(100MHz,CDCl3)δ156.0,132.3(q,J＝32.4Hz),130.7, 123.8(q,J＝270.8Hz),119.1(q,J＝3.7Hz),117.9,111.8(q,J＝3.9Hz),64.9,59.6；19F NMR (376MHz,CDCl3)δ29.6(s,1F),-62.3(s,3F)；GC-MS(tR):9.7min；EI-MS(m/z):299[M]+(ii) a HRMS (EI, m/z) calculated C10H9NO3F4S:299.0239[M]+The actual value is 299.0244.
Example 58
Preparation of 4-benzoylaminopiperidine-1-sulfonyl fluoride
Preparation of Scheme 584-benzoylaminopiperidine-1-sulfonyl fluoride
Dissolving 4-benzoylaminopiperidine hydrate [ compound 123] (204mg,1mmol) in tetrahydrofuran (5mL) at room temperature, adding 1- (fluorosulfonyl) -2, 3-dimethyl-1H-imidazole trifluoromethanesulfonate [ compound 4] (328mg,1mmol), reacting for 2 hours, detecting by LC-MS that the reaction is completed, adding water (30mL) to the reaction solution, extracting with ethyl acetate (20mL × 3), combining the organic phases, washing with water (20mL) and saturated saline (20mL), drying with anhydrous sodium sulfate, filtering with filter paper, concentrating the filtrate by a rotary evaporator, purifying by column chromatography (silica gel 300-400 mesh, petroleum ether: ethyl acetate ═ 2:1) to obtain a white solid 4-benzoylaminopiperidine-1-sulfonylfluoride [ compound 124] (200mg, 70%) (Scheme 58).
White solid, m.p.205-207 ℃,200mg, 70% yield;1H NMR(400MHz,DMSO-d6)δ8.40(d, J＝7.6Hz,1H),7.84(d,J＝7.2Hz,2H),7.53(t,J＝7.2Hz,1H),7.47(t,J＝7.6Hz,2H),4.06(m,1H),3.82(d,J＝13.2Hz,2H),3.33(dt,J＝4.4Hz,J＝15.2Hz,2H),1.95(dd,J＝2.4Hz,J＝13.2Hz,2H),1.67(dq,J＝4Hz,J＝12Hz,2H)；13C NMR(100MHz,DMSO-d6)δ165.9, 134.5,131.2,128.2,127.4,46.2,45.1,30.0；19F NMR(MHz,DMSO-d6)δ43.8(s,1F)；LC-MS (tR):1.4min；ESI-MS(m/z):287[MH]+(ii) a HRMS (DART, m/z) calculated value C12H16N2O3FS: 287.0860[MH]+The actual value is 287.0860.
Example 59
Preparation of 3- (3,4, 5-trimethoxybenzamido) piperidine-1-sulfonyl fluoride
Preparation of Scheme 593- (3,4, 5-trimethoxybenzamido) piperidine-1-sulfonyl fluoride
1- (fluorosulfonyl) -2, 3-dimethyl-1H-imidazole trifluoromethanesulfonate [ compound 4] (164mg,0.5mmol) was dissolved in acetonitrile (5mL) at room temperature, troxipide [ compound 125] (148mg,0.5mmol) was added, the reaction was carried out for 1 hour, and after completion of the detection by LC-MS, purification was carried out by column chromatography (silica gel 300-400 mesh, dichloromethane: ethyl acetate 10:1) to obtain 3- (3,4, 5-trimethoxybenzamido) piperidine-1-sulfonylfluoride [ compound 126] (184mg, 98%) as a white solid (Scheme 59).
White solid, m.p.184-186 ℃,184mg, 98% yield;1H NMR(400MHz,DMSO-d6)δ8.33(d, J＝6.8Hz,1H),7.16(s,2H),3.98(m,1H),3.86(m,1H),3.83(s,6H),3.73(m,1H),3.70(s,3H),3.19(t,J＝11.6Hz,1H),3.05(m,1H),1.94(t,J＝10Hz,2H),1.65(sext,J＝10Hz,2H)；13C NMR(100MHz,DMSO-d6)δ165.8,152.5,140.2,129.3,105.1,60.1,56.0,50.1,47.0,45.4, 28.2,22.8；19F NMR(MHz,DMSO-d6)δ43.8(s,1F)；LC-MS(tR):1.4min；ESI-MS(m/z):377 [MH]+(ii) a HRMS (DART, m/z) calculated value C15H22N2O6FS:377.1177[MH]+The actual value is 377.1175.
Example 60
Preparation of N-fluorosulfonyl fluoxetine
Preparation of Scheme 60N-fluorosulfonyl fluoxetine
Triethylamine (69. mu.L, 0.5mmol) was added to a solution of fluoxetine hydrochloride [ Compound 127(173mg,0.5mmol) in dichloromethane (4mL) at room temperature, stirred at room temperature for 5 minutes, and then 1- (fluorosulfonyl) -2, 3-dimethyl-1H-imidazole trifluoromethanesulfonate [ Compound 4] was added](164mg,0.5mmol), stirred at rt for 1h, TLC (petroleum ether 60-90: ethyl acetate 9:1, product RfNo. 0.4) detection reaction was complete. Purifying by column chromatography (silica gel 300-400 mesh, petroleum ether 60-90: ethyl acetate 6:1) to obtain white solid N-fluorosulfonyl fluoxetine [ compound 128 ]](152mg,85％)(Scheme 60)。
White solid, m.p125-127 ℃,152mg, 85% yield;1HNMR(400MHz,CD3CN)δ7.50(d,J＝9Hz,2H),7.43-7.28(m,5H),7.00(d,J＝9Hz,2H),5.41(dd,J＝9Hz,J＝4Hz,1H),3.63(m, 1H),3.52(m,1H),3.02(d,J＝2Hz,3H),2.25(m,2H)；13C NMR(100MHz,CD3CN)δ161.4, 141.3,129.8,129.2,127,7(q,J＝4Hz),127.1,125.6(q,J＝269Hz),123.3(q,J＝32Hz),117.2, 77.8,49.2,36.8,36.5；19F NMR(376MHz,CD3CN) δ 41.7(d, J ═ 2Hz,1F), -60.8(s,3F), HRMS (DART, m/z): calculated value C17H21F4N2O3S:409.1204[M+NH4]+The actual value is 409.1201.
Example 61
Preparation of N-fluorosulfonyl amoxapine
Preparation of Scheme 61N-fluorosulfonyl amoxapine
1- (fluorosulfonyl) -2, 3-dimethyl-1H-imidazole trifluoromethanesulfonate [ compound 4]](164mg,0.5mmol) Amoxapine [ Compound 129 ] was added](157mg,0.5mmol) in dichloromethane (5mL) stirred at rt for 1h, TLC (petroleum ether 60-90: ethyl acetate 3:1, product RfNo. 0.7) detection reaction was complete. Purifying by column chromatography (silica gel 300-400 mesh, petroleum ether 60-90: ethyl acetate 4:1) to obtain white solid N-fluorosulfonyl amoxapine [ compound 130-] (188mg,95％)(Scheme 61)。
White solid, m.p.147-150 ℃,188mg, 95% yield;1H NMR(400MHz,CD3CN)δ7.54-7.03 (m,7H),3.60(m,8H)；13C NMR(100MHz,CD3CN)δ160.4,159.6,152.7,140.8,134.2,131.3, 129.9,127.9,127.0,126.2,125.5,123.9,121.3,47.5,47.0；19F NMR(376MHz,CD3CN) delta 39.4(s) HRMS (DART, m/z) calculated C17H16ClFN3O3S:396.0579[MH]+The actual value is 396.0577.
Example 62
Preparation of 1, 4-bis (fluorosulfonyl) piperazine
Preparation of Scheme 621, 4-bis (fluorosulfonyl) piperazine
1- (fluorosulfonyl) -2, 3-dimethyl-1H-imidazole trifluoromethanesulfonate [ compound 4] (656mg,2.0mmol) was added to a solution of piperazine [ compound 131] (86mg,1.0mmol) in methylene chloride (5mL), and the mixture was stirred at room temperature for 2 hours and then TLC was performed to detect completion of the reaction. The reaction solution was concentrated by a rotary evaporator, ethyl acetate (25mL) was added, the organic phase was washed with 2M hydrochloric acid (20mL), 0.1M hydrochloric acid (20mL × 2), water (20mL), saturated brine (10mL × 2), dried over anhydrous sodium sulfate, filtered through filter paper, the filtrate was concentrated by a rotary evaporator, and the solvent was pumped off by an oil pump to give 1, 4-bis (fluorosulfonyl) piperazine [ compound 132] (200mg, 81%) (Scheme 62) as a white solid.
White solid, m.p.246-248 ℃,200mg, 81% yield;1H NMR(400MHz,(CD3)2CO)δ3.76(s)；13C NMR(100MHz,(CD3)2CO)δ46.8；19F NMR(376MHz,(CD3)2CO) delta 41.2(s) HRMS (DART, m/z) calculated C4H7F2N2O4S:248.9821[M-H]-The actual value is 248.9820.
Example 63
Preparation of (S) -2-benzyl-aziridine-1-sulfonyl fluoride
Preparation of Scheme 63(S) -2-benzyl-aziridine-1-sulfonyl fluoride
S-2-benzylaziridine [ compound 133] (266mg,2mmol) was dissolved in acetonitrile (3mL) at room temperature, 1- (fluorosulfonyl) -2, 3-dimethyl-1H-imidazole trifluoromethanesulfonate [ compound 4] (656mg,2mmol) was added, the reaction was carried out for 2 hours, GC-MS monitored for good reaction, and work-up (addition of water (30mL) to the reaction solution, extraction with ethyl acetate (20 mL. times.3), combination of organic phases, washing with water (20mL), saturated brine (20mL), drying over anhydrous sodium sulfate, filter paper filtration, concentration of the filtrate by a rotary evaporator, and oil pump-out of the solvent) did not yield the desired product.
GC-MS(tR):8.3min；EI-MS(m/z):215[M]+.
Example 64
Preparation of benzylaminosulfonyl fluorides
Preparation of Scheme 64 benzylamine sulfonyl fluoride
Benzylamine [ compound 135] (1.07g,10mmol) was dissolved in acetonitrile (10mL), and 1- (fluorosulfonyl) -2, 3-dimethyl-1H-imidazole trifluoromethanesulfonate [ compound 4] (3.28g,10mmol) was added under ice-cooling, after completion of the reaction, the ice-cooling was removed, the reaction was carried out at room temperature for 4 hours, and after completion of the reaction was detected by GC-MS, water (50mL) was added to the reaction solution, ethyl acetate (30mL × 3) was extracted, the organic phases were combined and washed with water (30mL) and saturated brine (30mL), dried over anhydrous sodium sulfate, filtered through filter paper, the filtrate was concentrated by a rotary evaporator, and the solvent was pumped out by an oil pump to obtain benzylamine sulfonyl fluoride [ compound 136] (1.6g, 84%) (Scheme 64) as a yellow oil.
Yellow oil, 1.6g, 84% yield;1H NMR(400MHz,CDCl3)δ7.42-7.33(m,5H),5.15(br, 1H),4.45(d,J＝5.6Hz,2H)；13C NMR(100MHz,CDCl3)δ134.8,129.2,128.8,128.1,48.5；19F NMR(376MHz,CDCl3)δ50.4(s,1F)；GC-MS(tR):8.1min；EI-MS(m/z):189[M]+(ii) a HRMS (EI, m/z) calculated C7H8NO2FS:189.0260[M]+The actual value is 189.0259.
Example 65
Preparation of 4-phenyl-2-butylaminosulfonyl fluoride
Preparation of Scheme 654-phenyl-2-butyl amine sulfonyl fluoride
Dissolving 1-methyl-3-phenylpropylamine [ compound 137] (149mg,1mmol) in acetonitrile (3mL), adding 1- (fluorosulfonyl) -2, 3-dimethyl-1H-imidazole trifluoromethanesulfonate [ compound 4] (328mg,1mmol) under ice bath, removing ice bath after completion of the reaction, reacting at room temperature for 4 hours, detecting completion of the reaction by GC-MS, adding water (30mL) to the reaction solution, extracting with ethyl acetate (20 mL. times.3), combining the organic phases, washing with water (20mL) and saturated brine (20mL), drying over anhydrous sodium sulfate, filtering with filter paper, concentrating the filtrate by a rotary evaporator, and pumping off the solvent by an oil pump to obtain a yellow oily substance, namely 4-phenyl-2-butylaminosulfonyl fluoride [ compound 138] (207mg, 90%) (Scheme 65).
Yellow oil, 207mg, 90% yield;1H NMR(400MHz,CDCl3)δ7.30(t,J＝7.2Hz,2H),7.22 (d,J＝7.2Hz,1H),7.18(d,2H,J＝7.6Hz),4.91(br,1H),3.69(m,1H),2.71(m,2H),1.87(m,2H),1.33(d,J＝6.8Hz,3H)；13C NMR(100MHz,CDCl3)δ140.7,128.7,128.4,126.3,52.3, 38.5,31.9,21.3；19F NMR(376MHz,CDCl3)δ53.8(d,J＝5.6Hz,1F)；LC-MS(tR):1.62min； ESI-MS(m/z):230[M-H]-(ii) a HRMS (DART, m/z) calculated value C10H18N2O2FS:249.1068[M+NH4]+The actual value is 249.1067.
Example 66
Preparation of 2-phenyl-1-ethylamine sulfonyl fluoride
Preparation of Scheme 662-phenyl-1-ethylamine sulfonyl fluoride
Dissolving 2-phenethylamine [ compound 139] (121mg,1mmol) in acetonitrile (3mL), adding 1- (fluorosulfonyl) -2, 3-dimethyl-1H-imidazole trifluoromethanesulfonate [ compound 4] (328mg,1mmol) under ice bath, removing ice bath after completion of the reaction, reacting at room temperature for 4 hours, detecting completion of the reaction by GC-MS, adding water (30mL) to the reaction solution, extracting with ethyl acetate (20 mL. times.3), combining the organic phases, washing with water (20mL) and saturated saline (20mL), drying with anhydrous sodium sulfate, filtering with filter paper, concentrating the filtrate by a rotary evaporator, and pumping off the solvent by an oil pump to obtain a yellow oily 2-phenyl-1-ethylamine sulfonyl fluoride [ compound 140] (196mg, 97%) (Scheme 66).
Yellow oil, 196mg, 97% yield;1H NMR(400MHz,CDCl3)δ7.38-7.20(m,5H),4.88(br, 1H),3.57(q,J＝6.8Hz,2H),2.94(t,J＝6.8Hz,2H)；13C NMR(100MHz,CDCl3)δ136.9, 129.0,128.9,127.3,45.6,35.5；19F NMR(376MHz,CDCl3)δ51.1(s,1F)；LC-MS(tR):1.51 min；ESI-MS(m/z):202[M-H]-(ii) a HRMS (DART, m/z) calculated value C8H14N2O2FS:221.0755 [M+NH4]+The actual value is 221.0754.
Example 67
Preparation of 2-phenoxy-1-ethylamine sulfonyl fluoride
Preparation of Scheme 672-phenoxy-1-ethyl amine sulfonyl fluoride
Dissolving 2-phenoxyethylamine [ compound 141] (137mg,1mmol) in acetonitrile (3mL), adding 1- (fluorosulfonyl) -2, 3-dimethyl-1H-imidazole trifluoromethanesulfonate [ compound 4] (328mg,1mmol) under ice bath, removing ice bath after completion of the reaction, reacting at room temperature for 4 hours, detecting completion of the reaction by GC-MS, adding water (30mL) to the reaction solution, extracting with ethyl acetate (20 mL. times.3), combining the organic phases, washing with water (20mL) and saturated saline (20mL), drying with anhydrous sodium sulfate, filtering with filter paper, concentrating the filtrate by a rotary evaporator, and pumping out the solvent by an oil pump to obtain pale yellow solid 2-phenoxy-1-ethylamine sulfonyl fluoride [ compound 142] (203mg, 92%) (Scheme 67).
Pale yellow solid, m.p.46-49 ℃,203mg, 92% yield;1H NMR(400MHz,CDCl3)δ7.32(t,J ＝8Hz,2H),7.02(t,J＝7.6Hz,1H),6.89(d,J＝7.6Hz,2H),5.51(br,1H),4.13(t,J＝4.8Hz,2H),3.69(m,2H)；13C NMR(100MHz,CDCl3)δ157.9,129.8,121.9,114.6,65.6,44.0；19F NMR(376MHz,CDCl3)δ51.1(s,1F)；LC-MS(tR):1.48min；ESI-MS(m/z):218[M-H]-(ii) a HRMS (DART, m/z) calculated value C8H14N2O3FS:237.0704[M+NH4]+The actual value is 237.0703.
Example 68
Preparation of (1, 1' -biphenyl) -4-methylaminosulfonyl fluoride
Preparation of Scheme 68(1, 1' -biphenyl) -4-methylaminosulfonyl fluoride
4-phenylbenzylamine [ compound 143] (183mg,1mmol) was dissolved in acetonitrile (3mL), and 1- (fluorosulfonyl) -2, 3-dimethyl-1H-imidazole trifluoromethanesulfonate [ compound 4] (328mg,1mmol) was added under ice-cooling, after completion of the ice-cooling, the ice-cooling was removed, the reaction was carried out at room temperature for 4 hours, completion of the reaction was detected by LC-MS, water (30mL) was added to the reaction solution, ethyl acetate (20 mL. times.3) was extracted, the organic phases were combined, washed with water (20mL), a saturated NaCl solution (20mL) was used, dried over anhydrous sodium sulfate, filtered through filter paper, the filtrate was concentrated by a rotary evaporator, and the solvent was pumped out by an oil pump to obtain a pale yellow solid (1, 1' -biphenyl) -4-methylaminosulfonyl fluoride [ compound 144] (246mg, 93%) (Scheme 68).
Pale yellow solid, m.p.107-111 ℃,246mg, 93% yield;1H NMR(400MHz,CDCl3)δ7.60(m, 4H),7.41(m,5H),5.20(br,1H),4.49(d,J＝5.6Hz,2H)；13C NMR(100MHz,CD3CN)δ141.7, 141.2,136.2,129.9,129.6,128.6,128.2,127.9,48.2；19F NMR(376MHz,CDCl3)δ50.6(s,1F)； LC-MS(tR):1.64min；ESI-MS(m/z):264[M-H]-, HRMS (DART, m/z): calculation C13H16N2O2FS:283.0911[M+NH4]+The actual value is 283.0911.
Example 69
Preparation of naphthyl-1-methylamine sulfonyl fluoride
Preparation of Scheme 69 naphthyl-1-methylamine sulfonyl fluoride
Dissolving 1-naphthylmethylamine [ compound 145] (157mg,1mmol) in acetonitrile (3mL), adding 1- (fluorosulfonyl) -2, 3-dimethyl-1H-imidazole trifluoromethanesulfonate [ compound 4] (328mg,1mmol) under ice bath, removing ice bath after completion of the reaction, reacting at room temperature for 4 hours, detecting completion of the reaction by LC-MS, adding water (30mL) to the reaction solution, extracting with ethyl acetate (20 mL. times.3), combining organic phases, washing with water (20mL) and saturated saline (20mL), drying with anhydrous sodium sulfate, filtering with filter paper, concentrating the filtrate by a rotary evaporator, and pumping off the solvent by an oil pump to obtain a light yellow solid, namely naphthyl-1-sulfonylfluoride [ compound 146] (223mg, 93%) (Scheme 69).
Pale yellow solid, m.p.68-71 ℃,223mg, 93% yield;1H NMR(400MHz,CDCl3)δ8.00(d,J＝ 8.4Hz,1H),7.90(t,J＝8.4Hz,2H),7.64-7.44(m,4H),5.14(br,1H),4.89(d,J＝5.2Hz,2H)；13CNMR(100MHz,CDCl3)δ133.9,130.9,129.9,129.9,129.1,127.5,127.3,126.4,125.4, 122.7,46.5；19F NMR(376MHz,CDCl3)δ49.5(s,1F)；LC-MS(tR):1.57min；ESI-MS(m/z): 238[M-H]-, HRMS (DART, m/z): calculation C11H14N2O2FS:257.0755[M+NH4]+The actual value is 257.0754.
Example 70
Preparation of (S) - (-) -1- (1-naphthyl) ethansulfonyl fluoride
Preparation of Scheme 70(S) - (-) -1- (1-naphthyl) ethansulfonyl fluoride
Dissolving (S) - (-) -1- (1-naphthyl) ethylamine [ compound 147] (171mg,1mmol) in acetonitrile (3mL), adding 1- (fluorosulfonyl) -2, 3-dimethyl-1H-imidazole trifluoromethanesulfonate [ compound 4] (328mg,1mmol) under ice bath, removing ice bath, reacting at room temperature for 4 hours, detecting reaction completion by LC-MS, adding water (30mL) to the reaction solution, extracting with ethyl acetate (20 mL. times.3), combining the organic phases, washing with water (20mL), saturated brine (20mL), drying with anhydrous sodium sulfate, filtering with filter paper, concentrating the filtrate by rotary evaporator, pumping off the solvent with oil pump to obtain a pale yellow solid (S) - (-) -1- (1-naphthyl) ethylamine sulfonyl fluoride [ compound 148] (252mg, 99%) (Scheme 70).
Pale yellow solid, 252mg, m.p.69-71 ℃, 99% yield;1H NMR(400MHz,CDCl3)δ8.10(d,J ＝8.4Hz,1H),7.91(d,J＝8Hz,1H),7.86(d,J＝8Hz,1H),7.63-7.46(m,4H),5.60(quin,J＝6.8Hz,1H),5.28(br,1H),1.82(d,J＝6.8Hz,3H)；13C NMR(100MHz,CDCl3)δ135.7,135.7, 134.0,130.3,129.3,129.2,127.1,126.2,125.4,123.2,122.5,51.5,21.9；19F NMR(376MHz, CDCl3)δ54.2(s,1F)；LC-MS(tR):1.59min；ESI-MS(m/z):252[M-H]-, HRMS (DART, m/z): calculation C12H16N2O2FS:271.0911[M+NH4]+The actual value is 271.0910.
Example 71
Preparation of (N-fluorosulfonyl) -2-hydroxybenzylamine
Preparation of Scheme 71N-fluorosulfonyl-2-hydroxybenzylamine
1- (fluorosulfonyl) -2, 3-dimethyl-1H-imidazole trifluoromethanesulfonate [ compound 4]](328mg,1.0mmol) 2-hydroxybenzylamine [ Compound 149 ] was added](123mg,1.0mmol) in acetonitrile (6mL), stirred at room temperature for 2h, TLC (petroleum ether 60-90: ethyl acetate 9:1, product RfNo. 0.5) detection reaction was complete. Purifying by column chromatography (silica gel 300-400 mesh, petroleum ether 60-90: ethyl acetate 9:1) to obtain white solid (N-fluorosulfonyl) -2-hydroxybenzylamine [ compound 150-](97mg,47％)(Scheme 71)。
White solid, m.p.64-67 ℃,97mg, 47% yield;1H NMR(400MHz,CD3CN)δ7.26-6.86(m, 6H),4.37(s,2H)；13C NMR(100MHz,(CD3)2CO)δ156.1,130.6,130.3,123.3,120.5,116.0, 44.0；19F NMR(376MHz,(CD3)2CO) delta 50.6(s) HRMS (DART, m/z) calculated C7H7FNO3S: 204.0136[M-H]-The actual value is 204.0133.
Example 72
Preparation of N-fluorosulfonyl tyramine
Preparation of Scheme 72N-fluorosulfonyl tyramine
1- (fluorosulfonyl) -2, 3-dimethyl-1H-imidazole trifluoromethanesulfonate [ compound 4]](328mg,1.0mmol) tyramine [ Compound 151 ] was added](137mg,1.0mmol) in acetonitrile (6mL), stirred at room temperature for 2h, TLC (dichloromethane: ethyl acetate: 6:1, product R)fNo. 0.5) detection reaction was complete. Purifying by column chromatography (silica gel 300-400 mesh, dichloromethane: ethyl acetate 6:1) to obtain white solid N-fluorosulfonyl tyramine [ compound 152 ]](138mg,63％) (Scheme 72)。
White solid, m.p.90-92 ℃,138mg, 63% yield;1H NMR(400MHz,CD3CN)δ7.08(d,J＝ 8Hz,2H),6.82(br,1H),6.76(d,J＝8Hz,2H),6.62(br,1H),3.41(m,2H),2.78(t,J＝7Hz,2H)；13C NMR(100MHz,(CD3)2CO)δ157.1,130.7,129.5,116.3,46.7,35.5；19F NMR(376 MHz,(CD3)2CO) delta 50.8(s) HRMS (DART, m/z) calculated C8H9FNO3S:218.0293[M-H]-The actual value is 218.0290.
Example 73
Preparation of tert-butyl (R) -2- (fluorosulfonyl) amino-2-phenylacetate
Preparation of Scheme 732- (fluorosulfonyl) amino-2-phenylacetic acid tert-butyl ester
(R) -2-amino-2-phenylacetic acid tert-butyl ester [ compound 153 ] was placed in an ice bath](1.45g,7.0mmol) in acetonitrile (3mL) was added dropwise 1- (fluorosulfonyl) -2, 3-dimethyl-1H-imidazole trifluoromethanesulfonate [ Compound 4]](2.62g, 8.0mmol) in acetonitrile (2mL), after the addition was complete, the ice bath was removed, the mixture was stirred at room temperature for 10 minutes, TLC (petroleum ether: ethyl acetate: 5:1, product R)f0.7), adding water (30mL) to the reaction solution, extracting with ethyl acetate (25mL × 2), combining the organic phases, washing with water (20mL) and saturated brine (10mL × 2), drying over anhydrous sodium sulfate, filtering through a filter paper, concentrating the filtrate through a rotary evaporator, and pumping off the solvent with an oil pump to obtain (R) -2- (fluorosulfonyl) amino-2-benzene as a white solidTert-butyl acetoacetate [ compound 154](1.97g,97％)(Scheme 73)。
White solid, m.p.81-84 ℃,1.97g, 97% yield;1H NMR(400MHz,CDCl3)δ7.41-7.33(m, 5H),6.27(br,1H),5.11(s,1H),1.41(s,9H)；13C NMR(100MHz,CDCl3)δ168.4,134.8,129.1, 129.1,127.0,84.7,60.8,27.7；19F NMR(376MHz,CDCl3)δ52.9(s)；LC-MS(tR):1.62min； ESI-MS(m/z):232[M-tBu]-.
example 74
Preparation of 2- (4-fluorophenyl) -1, 1-dimethylethanesulfonyl fluoride
Preparation of Scheme 742- (4-fluorophenyl) -1, 1-dimethylethanesulfonyl fluoride
1- (fluorosulfonyl) -2, 3-dimethyl-1H-imidazole trifluoromethanesulfonate [ compound 4]](164mg,0.5mmol) was dissolved in acetonitrile (2mL) and 2- (4-fluorophenyl) -1, 1-dimethylethylamine [ compound 155](84mg,0.5mmol), stirring at room temperature for 0.5 h, TLC (petroleum ether: ethyl acetate 4:1, product R)fNo. 0.8), water (15mL) was added to the reaction solution, ethyl acetate (15mL × 2) was extracted, the organic phases were combined, washed with water (10mL) and saturated brine (5mL × 2), dried over anhydrous sodium sulfate, filtered through filter paper, the filtrate was concentrated by a rotary evaporator, and the solvent was pumped off by an oil pump to obtain 2- (4-fluorophenyl) -1, 1-dimethylethanesulfonyl fluoride [ compound 156 ] as a yellow oil](113mg,91％)(Scheme 74)。
Yellow oil, 113mg, 91% yield;1H NMR(400MHz,CDCl3)δ7.15(m,2H),7.02(m,2H), 4.68(br,1H),2.90(s,2H),1.38(s,6H)；13C NMR(100MHz,CDCl3)δ162.1(d,J＝244Hz), 132.1(d,J＝7Hz),131.6(d,J＝3Hz),115.3(d,J＝22Hz),58.9(s),46.3(d,J＝2Hz),26.9(s)；19F NMR(376MHz,CDCl3)δ59.4(s,1F),-115.9(s,1F)；GC-MS(tR):14.7min；EI-MS (m/z):249[M]+.
example 75
Preparation of (1R,2R) -1-benzyloxy-2-fluorosulfonylaminocyclopentane
Preparation of Scheme 75(1R,2R) -1-benzyloxy-2-fluorosulfonylaminocyclopentane
1- (fluorosulfonyl) -2, 3-dimethyl-1H-imidazole trifluoromethanesulfonate [ compound 4]](328mg,1.0mmol) was dissolved in acetonitrile (3mL), and (1R,2R) -1-benzyloxy-2-aminocyclopentane [ compound 157 ] was added](191mg,1.0mmol), stirring at room temperature for 0.5 h, TLC (petroleum ether: ethyl acetate 10:1, product R)f0.6), adding water (20mL) into the reaction solution, extracting with ethyl acetate (20mL × 2), and purifying by column chromatography (silica gel 300-: ethyl acetate 15:1) to give (1R,2R) -1-benzyloxy-2-fluorosulfonylaminocyclopentane [ compound 158 ] as a white solid](168mg,62％)(Scheme 75)。
White solid, m.p. 76-78 ℃,168mg, 62% yield;1H NMR(400MHz,CDCl3)δ7.39-7.28(m, 5H),4.86(br,1H),4.58(d,J＝12Hz,1H),4.53(d,J＝12Hz,1H),3.86(m,2H),2.25(m,1H),1.96(m,1H),1.87-1.65(m,3H),1.59(m,1H)；13C NMR(100MHz,CDCl3)δ137.9,128.5, 127.9,127.8,84.0,71.5,61.1,30.2,29.4,20.8；19F NMR(376MHz,CDCl3)δ52.0(s)；GC-MS (tR):18.9min；EI-MS(m/z):273[M]+.
example 76
Preparation of N-fluorosulfonylvaline benzyl ester
Preparation of Scheme 76N-fluorosulfonyl valine benzyl ester
(S) -valine benzyl ester hydrochloride [ compound 159](122mg,0.5mmol) was dissolved in acetonitrile (2.5mL), anhydrous sodium carbonate (106mg,1.0mmol) was added, stirring at room temperature for 16 hours, the solid was removed by filtration, and 1- (fluorosulfonyl) -2, 3-dimethyl-1H-imidazole trifluoromethanesulfonate [ compound 4] was added](164mg,0.5mmol) at room temperature for 1 hour, TLC (petroleum ether: ethyl acetate 5:1, product R)f0.7), water (20mL) was added to the reaction solution, ethyl acetate (20mL × 2) was extracted, the organic phase was washed with water (10mL) and saturated brine (5mL × 2), dried over anhydrous sodium sulfate, filtered through filter paper, the filtrate was concentrated by a rotary evaporator, and the solvent was drained by an oil pump to obtain N-fluorosulfonylvaline benzyl ester [ compound 161 ] as a colorless liquid](137mg,94％)(Scheme 76)。
Colorless oil, 137mg, 94% yield;1H NMR(400MHz,CDCl3)δ7.41-7.35(m,5H),5.26(d,J ＝12Hz,1H),5.21(d,J＝12Hz,1H),4.14(d,J＝4Hz,1H),2.24(m,1H),1.03(d,J＝7Hz,3H),0.86(d,J＝7Hz,3H)；13C NMR(100MHz,CDCl3)δ170.6,134.6,128.9,128.8,128.7, 68.2,62.4,31.4,18.7,16.9；19F NMR(376MHz,CDCl3)δ51.5；GC-MS(tR):17.4min；EI-MS (m/z):289[M]+.
example 77
Preparation of tert-butyl 3- (4- (tert-butoxy) phenyl) -2- (fluorosulfonyl) amino-propionate
Preparation of Scheme 773- (4- (tert-butoxy) phenyl) -2- (fluorosulfonyl) carbamic acid tert-butyl ester
The reaction product of tert-butyl (S) -3- (4- (tert-butoxy) phenyl) -2-aminopropionate [ Compound 162](165mg,0.5mmol) was dissolved in acetonitrile (2.5mL), anhydrous sodium carbonate (106mg,1.0mmol) was added, stirring at room temperature for 16 hours, the solid was removed by filtration, and 1- (fluorosulfonyl) -2, 3-dimethyl-1H-imidazole trifluoromethanesulfonate [ compound 4] was added](164mg,0.5mmol), stirred at rt for 1h, TLC (petroleum ether: ethyl acetate 5:1, product R)f0.7), adding water (20mL) to the reaction solution, extracting with ethyl acetate (20mL × 2), washing the organic phase with water (10mL) and saturated brine (5mL × 2), drying over anhydrous sodium sulfate, filtering with filter paper, concentrating the filtrate by a rotary evaporator, and draining off the solvent with an oil pump to obtain colorless liquid tert-butyl 3- (4- (tert-butoxy) phenyl) -2- (fluorosulfonyl) amino propionate [ compound 164- (tert-butyl) amide ]](186mg,99％)(Scheme 77)。
Colorless liquid, 186mg, 99% yield;1H NMR(400MHz,CDCl3)δ7.08(d,J＝8Hz,2H),6.93 (d,J＝8Hz,2H),5.56(s,1H),4.36(t,J＝6Hz,1H),3.16-3.05(m,2H),1.41(s,9H),1.33(s,9H)；13C NMR(100MHz,CDCl3)δ169.0,154.7,130.1,129.3,124.3,84.0,78.6,58.3,38.1, 28.8,27.8；19F NMR(376MHz,CDCl3)δ52.2；GC-MS(tR):20.9min；EI-MS(m/z):360[M- Me]+.
example 78
Preparation of N-fluorosulfonyl-alpha, alpha-dimethylbenzylamine
Preparation of Scheme 78N-fluorosulfonyl-alpha, alpha-dimethylbenzylamine
Mixing sesamin [ compound 165 ]](135mg,1.0mmol) was dissolved in acetonitrile (5.0mL) and 1- (fluorosulfonyl) -2, 3-dimethyl-1H-imidazole trifluoromethanesulfonate [ Compound 4] was added](328mg,1.0mmol), stirred at room temperature for 1h, TLC (petroleum ether 60-90: ethyl acetate 9:1, product RfNo. 0.5), water (20mL) was added to the reaction solution, ethyl acetate (30mL) was extracted, the organic phase was washed with water (20mL × 2) and saturated brine (10mL × 2), dried over anhydrous sodium sulfate, filtered through filter paper, the filtrate was concentrated by rotary evaporator, and the solvent was pumped off by an oil pump to obtain a pale yellow liquid N-fluorosulfonyl- α, α -dimethylbenzylamine [ compound 166: 166 ] as a reaction product](160mg,74％)(Scheme 78)。
Light yellow liquid, 160mg, 74% yield;1H NMR(400MHz,CD3CN)δ7.51-7.28(m,5H),7.13 (br,1H),1.71(s,6H)；13C NMR(100MHz,CD3CN)δ146.0,129.3,128.3,126.4,61.2,29.7；19F NMR(376MHz,CD3CN) delta 59.7 HRMS (DART, m/z): calculated value C9H16FN2O2S:235.0909 [M+NH4]+The actual value is 235.0911.
Example 79
Preparation of (S) -N-fluorosulfonyl-alpha-methylphenylalanine methyl ester
Preparation of Scheme 79(S) -N-fluorosulfonyl-alpha-methylphenylalanine methyl ester
The (S) -alpha-methyl phenylalanine methyl ester hydrochloride [ compound 167](230mg,1.0mmol) was added 0.25M aqueous sodium hydroxide solution (4mL), followed by dichloromethane (5mL), stirred at room temperature for 5 minutes, and then 1- (fluorosulfonyl) -2, 3-dimethyl-1H-imidazole trifluoromethanesulfonate [ Compound 4] was added to the organic phase](328mg,1.0mmol) in acetonitrile (8ml) and stirred at room temperature for 0.5 h, TLC (Petroleum ether 60-90: ethyl acetate 9:1, product R)fNo. 0.4), the reaction solution was concentrated by a rotary evaporator, ethyl acetate (20mL) was added, the organic phase was washed with water (20mL × 2) and saturated brine (10mL × 2), dried over anhydrous sodium sulfate, filtered with filter paper, the filtrate was concentrated by a rotary evaporator, and the solvent was pumped off by an oil pump to obtain (S) -N-fluorosulfonyl- α -methylphenylalanine methyl ester [ compound 168.4) ] as a yellow liquid](205mg,75％) (Scheme 79)。
Yellow liquid, 205mg, 75% yield;1H NMR(400MHz,CDCl3)δ7.32-7.11(m,5H),6.02(br, 1H),3.35(d,J＝14Hz,1H),3.13(d,J＝14Hz,1H),1.83(s,3H)；13C NMR(100MHz,CDCl3) δ172.4,134.5,129.9,128.7,127.7,64.8,53.5,44.1,22.9；19F NMR(376MHz,CDCl3) Delta 60.3 HRMS (DART, m/z): calculated value C11H13FNO4S:274.0548[M-H]-The actual value is 274.0555.
Example 80
Preparation of (R) -N-fluorosulfonyl p-methylsulfonyl phenylserine ethyl ester
Preparation of Scheme 80(R) -N-fluorosulfonyl p-methylsulfonyl phenylserine ethyl ester
The (R) -p-methylsulfonyl phenyl serine ethyl ester [ compound 169](287mg,1.0mmol) of 1- (fluorosulfonyl) -2, 3-dimethyl-1H-imidazole trifluoromethanesulfonate [ 2], [ solution ] was addedCompound 4](328mg,1.0mmol) in acetonitrile (8mL) and stirred at room temperature for 1h, TLC (petroleum ether 60-90: ethyl acetate 1:2, product R)f0.5), adding water (25mL) to the reaction solution, extracting with ethyl acetate (30mL), washing the organic phase with 0.1M hydrochloric acid (20mL × 2) and saturated brine (10mL × 2), drying over anhydrous sodium sulfate, filtering through a filter paper, concentrating the filtrate through a rotary evaporator, and pumping off the solvent with an oil pump to obtain a white solid of (R) - (N-fluorosulfonyl) p-methylsulfonylphenylserine ethyl ester [ compound 170 ]](267 mg,72％)(Scheme 80)。
White solid, decompensation at 136 ℃,267mg, 72% yield;1H NMR(400MHz,CD3CN) δ7.92(d,J＝8Hz,2H),7.67(d,J＝8Hz,2H),7.38(br,1H),5.41(d,J＝3Hz,1H),4.41(d,J ＝3Hz,1H),4.26(m,3H),3.06(s,3H),1.27(t,J＝7Hz,3H)；13C NMR(100MHz,CD3CN)δ 169.6,147.6,141.9,128.9,128.6,73.3,64.8,63.8,45.0,14.9；19F NMR(376MHz,CD3CN) delta 53.6(s) HRMS (DART, m/z) calculated C12H15FNO7S2:368.0279[M-H]-The actual value is 368.0274.
Example 81
Preparation of 4-chloroanilino sulfonyl fluoride
Preparation of Scheme 814-chloroanilino sulfonyl fluoride
1- (fluorosulfonyl) -2, 3-dimethyl-1H-imidazole trifluoromethanesulfonate [ compound 4] (361mg,1.1mmol) was suspended in dichloromethane (10mL), p-chloroaniline [ compound 171] (128mg,1mmol) was added under ice-cooling, the ice-cooling was removed after completion, the reaction was carried out at room temperature for 4 hours, LC-MS detection was carried out after completion of the reaction, and purification was carried out by column chromatography (silica gel 300-400 mesh, dichloromethane: ethyl acetate ═ 20:1) to obtain 4-chloroaniline sulfonyl fluoride [ compound 172] (185mg, 88%) as a pale yellow solid (Scheme 81).
Pale yellow solid, m.p.44-48 ℃,185mg, 88% yield;1H NMR(400MHz,CDCl3)δ7.39(m, 2H),7.22(m,2H),7.06(br,1H)；13C NMR(100MHz,CDCl3)δ133.5(s),132.3(d,J＝3Hz), 130.0(s),124.6(d,J＝1Hz)；19F NMR(376MHz,CDCl3)δ50.5(s,1F)；LC-MS(tR):1.52min； ESI-MS(m/z):208[M-H]-(ii) a HRMS (DART, m/z) calculated value C6H4NO2ClFS:207.9641[M-H]-The actual value is 207.9639.
Example 82
Preparation of 4-fluoroaniline sulfuryl fluoride
Preparation of Scheme 824-fluoroaniline sulfonyl fluoride
1- (fluorosulfonyl) -2, 3-dimethyl-1H-imidazole trifluoromethanesulfonate [ compound 4] (361mg,1.1mmol) was suspended in dichloromethane (10mL), p-fluoroaniline [ compound 173] (111mg,1mmol) was added under ice-cooling, the ice-cooling was removed after completion, the reaction was carried out at room temperature for 4 hours, LC-MS detection showed completion, dichloromethane (20mL) was added to the reaction solution, the organic phase was washed with 0.1M hydrochloric acid (20 mL. times.3) and saturated saline (10 mL. times.2), dried over anhydrous sodium sulfate, filtered through filter paper, the filtrate was concentrated by a rotary evaporator, and the solvent was pumped off by an oil pump to give 4-fluoroaniline sulfonyl fluoride [ compound 174] (86mg, 44%) (Scheme 82) as a yellow oil.
Yellow oil, 86mg, 44% yield;1H NMR(400MHz,CDCl3)δ7.30(m,2H),7.11(m,2H), 7.03(br,1H)；13C NMR(100MHz,CDCl3)δ161.9(d,J＝247Hz),129.6(t,J＝3Hz),126.3 (dd,J＝9Hz,J＝2Hz),116.8(d,J＝23Hz)；19F NMR(376MHz,CDCl3)δ49.9(s,1F),-113.4 (quin,J＝4Hz,1F)；LC-MS(tR):1.43min；ESI-MS(m/z):192[M-H]-.
example 83
Preparation of 3-ethynyl anilinesulfonyl fluoride
Preparation of Scheme 833-ethynyl aniline sulfonyl fluoride
1- (fluorosulfonyl) -2, 3-dimethyl-1H-imidazole trifluoromethanesulfonate [ compound 4] (1807mg,5.5mmol) was suspended in dichloromethane (50mL), and 3-aminophenylacetylene [ compound 175] (586mg,5mmol) was added under ice bath, after completion of the ice bath, the ice bath was removed, reaction was carried out at room temperature for 4 hours, and LC-MS detection was completed, and purification was carried out by column chromatography (silica gel 300-400 mesh, dichloromethane: ethyl acetate ═ 30:1) to obtain 3-ethynylanilinesulfonyl fluoride [ compound 176] (882mg, 88%) as a yellow oil (Scheme 83).
Yellow oil, 882mg, 88% yield;1H NMR(400MHz,CDCl3)δ7.44-7.35(m,3H),7.28(m, 1H),7.08(br,1H),3.15(s,1H)；13C NMR(100MHz,CDCl3)δ134.0(d,J＝2Hz),131.1(s), 129.9(s),126.2(d,J＝2Hz),124.0(s),123.3(d,J＝1Hz),82.2(s),79.0(s)；19F NMR(376MHz, CDCl3)δ50.9(d,J＝4Hz,1F)；LC-MS(tR):1.46min；ESI-MS(m/z):198[M-H]-(ii) a HRMS (DART, m/z) calculated value C8H5NO2FS:198.0031[M-H]-The actual value is 198.0029.
Example 84
Preparation of 4-isopropylbenzenesulfonamide fluoride
Preparation of Scheme 844-isopropyl aniline sulfonyl fluoride
1- (fluorosulfonyl) -2, 3-dimethyl-1H-imidazole trifluoromethanesulfonate [ compound 4] (361mg,1.1mmol) was suspended in dichloromethane (10mL), 4-isopropylaniline [ compound 177] (135mg,1mmol) was added under ice-bath, the ice-bath was removed after completion, the reaction was carried out at room temperature for 4 hours, LC-MS detected completion of the reaction, dichloromethane (20mL) was added to the reaction solution, the organic phase was washed with 0.1M hydrochloric acid (20 mL. times.3) and saturated saline (10 mL. times.2), dried over anhydrous sodium sulfate, filtered through filter paper, the filtrate was concentrated by a rotary evaporator, and the solvent was pumped off by an oil pump to obtain 4-isopropylaniline sulfonyl fluoride [ compound 178] (191mg, 88%) (Scheme 84) as a purple oil.
Purple oil, 191mg, 88% yield;1H NMR(400MHz,CDCl3)δ7.24(m,4H),6.88(br,1H), 2.92(sept,J＝6.8Hz,1H),1.24(d,J＝6.8Hz,6H)；13C NMR(100MHz,CDCl3)δ148.7(s), 131.4(d,J＝2Hz),127.8(s),123.7(d,J＝2Hz),33.8(s),23.9(s)；19F NMR(376MHz,CDCl3) δ50.5(s,1F)；LC-MS(tR):1.61min；ESI-MS(m/z):216[M-H]-.
example 85
Preparation of 4-methoxyanilinesulfonyl fluoride
Preparation of Scheme 854-methoxyaniline sulfonyl fluoride
1- (fluorosulfonyl) -2, 3-dimethyl-1H-imidazole trifluoromethanesulfonate [ compound 4] (361mg,1.1mmol) was suspended in dichloromethane (10mL), p-anisidine [ compound 179] (123mg,1mmol) was added under ice-cooling, the ice-cooling was removed after completion, the reaction was carried out at room temperature for 4 hours, LC-MS detection of the completion of the reaction was carried out, dichloromethane (20mL) was added to the reaction solution, the organic phase was washed with 0.1M hydrochloric acid (20 mL. times.3) and saturated saline (10 mL. times.2), dried over anhydrous sodium sulfate, filtered through filter paper, the filtrate was concentrated by a rotary evaporator, and the solvent was pumped off by an oil pump to give 4-anisidine sulfonyl fluoride [ compound 180] (187mg, 91%) (Scheme 85) as a purple oil.
Purple oil, 187mg, 91% yield;1H NMR(400MHz,CDCl3)δ7.25(m,2H),6.92(m,2H), 6.82(br,1H),3.82(s,3H)；13C NMR(100MHz,CDCl3)δ159.3(s),126.8(d,J＝2Hz),126.2 (d,J＝2Hz),115.0(s),55.7(s)；19F NMR(376MHz,CDCl3)δ49.2(s,1F)；LC-MS(tR):1.41 min；ESI-MS(m/z):204[M-H]-.
example 86
Preparation of 3-methoxyanilinesulfonyl fluoride
Preparation of Scheme 863-methoxyaniline sulfonyl fluoride
1- (fluorosulfonyl) -2, 3-dimethyl-1H-imidazole trifluoromethanesulfonate [ compound 4] (361mg,1.1mmol) was suspended in dichloromethane (10mL), M-anisidine [ compound 181] (123mg,1mmol) was added under ice-bath, the ice-bath was removed after completion, the reaction was carried out at room temperature for 4 hours, LC-MS detection showed completion, dichloromethane (20mL) was added to the reaction solution, the organic phase was washed with 0.1M hydrochloric acid (20 mL. times.3) and saturated saline (10 mL. times.2), dried over anhydrous sodium sulfate, filtered through filter paper, the filtrate was concentrated by a rotary evaporator, and the solvent was pumped off by an oil pump to give 3-methoxyanilinesulfonylfluoride [ compound 182] (183mg, 89%) (Scheme 86) as a red oil.
Red oil, 183mg, 89% yield;1H NMR(400MHz,CDCl3)δ7.30(t,J＝8Hz,1H),7.22 (br,1H),6.84(m,3H),3.81(s,6H)；13C NMR(100MHz,CDCl3)δ160.5(s),135.1(d,J＝2 Hz),130.6(s),114.9(d,J＝2Hz),112.9(s),108.7(d,J＝2Hz),55.6(s)；19F NMR(376MHz, CDCl3)δ50.4(s,1F)；LC-MS(tR):1.43min；ESI-MS(m/z):204[M-H]-.
example 87
Preparation of 4-fluorosulfonyloxy-anilinesulfonyl fluoride
Preparation of Scheme 874-fluorosulfonyl oxyanilino sulfonyl fluoride
1- (fluorosulfonyl) -2, 3-dimethyl-1H-imidazole trifluoromethanesulfonate [ compound 4] (361mg,1.1mmol) was suspended in dichloromethane (10mL), and after completion of the addition of 4-aminophenoxysulfonyl fluoride [ compound 183] (191mg,1mmol) under ice-cooling, the ice-cooling was removed, reaction was carried out at room temperature for 4 hours, and after completion of the detection by LC-MS, purification was carried out by column chromatography (silica gel 300 and 400 mesh; dichloromethane: ethyl acetate ═ 20:1) to obtain 4-fluorosulfonyloxyaniline sulfonyl fluoride [ compound 184] (203mg, 74%) as a pale yellow solid (Scheme 87).
Pale yellow solid, m.p.106-111 ℃,203mg, 74% yield;1H NMR(400MHz,CD3CN)δ9.11(br, 1H),7.53(m,2H),7.47(m,2H)；13C NMR(100MHz,CD3CN)δ148.9(s),136.3(d,J＝3Hz), 125.1(d,J＝2Hz),123.5(d,J＝1Hz)；19F NMR(376MHz,CD3CN)δ50.7(s,1F),38.1(s, 1F)；LC-MS(tR):1.52min；ESI-MS(m/z):272[M-H]-(ii) a HRMS (DART, m/z) calculated value C6H4NO5F2S2:271.9504[M-H]-The actual value is 271.9501.
Example 88
This example examines the stability of 1- (fluorosulfonyl) -2, 3-dimethyl-1H-imidazole trifluoromethanesulfonate under various humidity environments
The experimental method comprises the following steps: the substance 1- (fluorosulfonyl) -2, 3-dimethyl-1H-imidazole trifluoromethanesulfonate was sampled (4.521g, 4.298g, 4.273g) respectively in three plastic bottles (20mL), the parafilm was sealed, and the three plastic bottles were placed in a laboratory bench (22 ℃ C.), a refrigerator (4 ℃ C.) and a desiccator (22 ℃ C.), respectively. Observations and tests were performed after 231 days, and the results are shown in table 1;
TABLE 1
In addition, after 231 days, three equal portions of triethylamine (220. mu.L, 1.59mmol) were added to 4-cinnamylphenol [ compound 32] separately at room temperature](225mg,1.04mmol) of acetonitrile (1mL) solution in three systems, after stirring for 10min, the substance 1- (fluorosulfonyl) -2-3-dimethyl-1H-imidazole trifluoromethanesulfonate [ compound 4] was placed in a laboratory bench (22 ℃), a refrigerator (4 ℃) and a dryer (22 ℃), respectively](425mg,1.29mmol) acetonitrile (1mL) solution was added to each system in one portion and reacted for 1h under argon protection, TLC (petroleum ether: ethyl acetate ═ 10:1, product Rf0.68) the reaction was followed. Purifying by column chromatography (silica gel 300-400 mesh, petroleum ether: ethyl acetate: 10:1) to obtain colorless liquid 4- (2-phenyl-2-propyl) phenoxysulfonyl fluoride [ compound 33-](scheme 88), the results are shown in Table 2:
TABLE 2
Preparation of Scheme 884- (2-phenyl-2-propyl) phenoxysulfonyl fluoride
Example 89
This example examines the melting range and thermal stability of 1- (fluorosulfonyl) -2, 3-dimethyl-1H-imidazole trifluoromethanesulfonate
The experimental method comprises the following steps: setting the temperature on a melting point instrument at 30-70 ℃, and measuring the melting range of the substance in the embodiment to be 62.1-64.2 ℃ with the temperature gradient of 0.5 ℃/min; the temperature is set at 129 ℃ and 240 ℃, the temperature rise gradient is 1.0 ℃/min, the material slowly foams at 135.2 ℃, changes from colorless to light yellow at 176.5 ℃, changes to yellow at 185.6 ℃, changes to dark yellow at 189.9 ℃ and changes to black at 199.4 ℃.
Example 90
This example investigates the stability of 1- (fluorosulfonyl) -2, 3-dimethyl-1H-imidazole trifluoromethanesulfonate in deionized water
The experimental method comprises the following steps: 1- (fluorosulfonyl) -2, 3-dimethyl-1H-imidazole trifluoromethanesulfonate (36mg,0.1 mmol) was dissolved in deionized water (1mL) at room temperature to prepare a solution, which was measured to have a pH of 1,19F-NMR traces the change of S-F signal of the solution, and the results are shown in Table 3:
TABLE 3
Example 91
Preparation of 1- (fluorosulfonyl) -2, 3-dimethyl-1H-imidazole fluorosulfonate
Preparation of Scheme 911- (fluorosulfonyl) -2, 3-dimethyl-1H-imidazole trifluoromethanesulfonate
To a suspension of sodium carbonate (5.31g,50mmol) in acetonitrile (20mL) at room temperature was added 2-methylimidazole [ compound 1]](1.65g,20mmol), the reaction system was pumped down by a water pumpAfter pressing, sulfuryl fluoride gas [ Compound 2] is introduced into the gas balloon](0.6L, 24mmol), stirring overnight, TLC (petroleum ether: ethyl acetate 10:1, product R)f0.44), filtering the reaction solution with silica gel (10-40 mesh), washing the filter cake with dichloromethane (40mL), extracting the filtrate with distilled water (100mL × 3), combining the aqueous phases, back-extracting with dichloromethane (40mL), combining the organic phases, washing with saturated brine (40mL), drying with anhydrous sodium sulfate, concentrating the filtrate with a rotary evaporator (the boiling point of 2-methyl-1H-imidazole-1-sulfonyl fluoride is low, the temperature is controlled below 20 ℃ during concentration, the pressure is controlled above 140 torr), and obtaining the product 2-methyl-1H-imidazole-1-sulfonyl fluoride [ compound 3] as a product]6.72g of a mixed solution of methylene chloride and acetonitrile was quantified using p-toluenesulfonyl fluoride, and the product was 3.07 g, i.e., 93.5% yield. Adding dichloromethane (18mL) into the prepared mixed solution under the protection of nitrogen, cooling to 0 ℃ in an ice bath, slowly dropwise adding methyl fluorosulfonate (1.5mL and 18.7mmol) by using a syringe under the stirring state, naturally melting the ice bath, returning to room temperature, reacting for 2 hours, detecting the completion of the reaction by LC-MS (liquid chromatography-mass spectrometry), concentrating the reaction solution to viscous oily matter by using a rotary evaporator, adding methyl tert-butyl ether (20mL), stirring to separate out a solid, pouring out the supernatant, washing the solid by using the methyl tert-butyl ether (20mL multiplied by 2), and draining the solvent by using an oil pump to obtain a white solid 1- (fluorosulfonyl) -2, 3-dimethyl-1H-imidazole fluorosulfonate [ compound 185]](4.78g,91.8％；overall yield 86％)(Scheme 91)。
White solid,m.p.172-176℃,4.77g,overall yield 86％；1H NMR(400MHz,CD3CN)δ 7.89(d,J＝2.8Hz,1H),7.60(d,J＝2.8Hz,1H),3.88(s,3H),2.87(s,3H)；13C NMR(100MHz, CD3CN)δ151.4,125.5,122.1,37.5,12.9；19F NMR(376MHz,CD3CN)δ61.4(s,1F),38.2(s, 1F)；HRMS(DART,m/z):Calcd.for C5H8O2N2FS:179.0285[M]+,Found:179.0287；HRMS (DART,m/z):Calcd.for O3FS:98.9558[M]-,Found:98.9562.
Example 92
Preparation of 1- (fluorosulfonyl) -2-methyl-1H-imidazole hydrogen sulfate
Preparation of Scheme 921- (fluorosulfonyl) -2-methyl-1H-imidazole hydrogen sulfate
To a suspension of sodium carbonate (5.31g,50mmol) in acetonitrile (20mL) at room temperature was added 2-methylimidazole [ compound 1]](1.64g,20mmol), the reaction system was pumped to negative pressure by a water pump, and sulfuryl fluoride gas [ Compound 2] was introduced into the reaction system through a balloon](0.6L, 24mmol), stirring overnight, TLC (petroleum ether: ethyl acetate 10:1, product R)f0.44), filtering the reaction solution with silica gel (10-40 mesh), washing the filter cake with dichloromethane (40mL), extracting the filtrate with distilled water (100mL × 3), combining the aqueous phases, back-extracting with dichloromethane (40mL), combining the organic phases, washing with saturated brine (40mL), drying with anhydrous sodium sulfate, concentrating the filtrate with a rotary evaporator (the boiling point of 2-methyl-1H-imidazole-1-sulfonyl fluoride is low, the temperature is controlled below 20 ℃ during concentration, the pressure is controlled above 140 torr), and obtaining the product 2-methyl-1H-imidazole-1-sulfonyl fluoride [ compound 3] as a product]5.89g of a mixed solution of methylene chloride and acetonitrile was quantified using p-toluenesulfonyl fluoride, and the product was 3.00 g, which was obtained in 91.5% yield. Adding dichloromethane (18mL) into the prepared mixed solution under the protection of nitrogen, cooling to 0 ℃ in an ice bath, slowly adding concentrated sulfuric acid (980 mu L,18.3mmol) dropwise by using a syringe under the stirring state, naturally melting in the ice bath, returning to room temperature, reacting for 2 hours, detecting the reaction completion by LC-MS, concentrating the reaction solution to viscous oily matter by using a rotary evaporator, adding methyl tert-butyl ether (30mL), stirring to separate out a solid, pouring out supernatant, washing the solid by using methyl tert-butyl ether (20mL multiplied by 2), and pumping out the solvent by using an oil pump to obtain a white solid 1- (fluorosulfonyl) -2-methyl-1H-imidazole bisulfate [ compound 186 ]](4.38g,91.3％；overall yield 83.5％)(Scheme 1)。
The temperature gradient of the melting point instrument is 1 ℃/min, the sample starts to melt at 99.2 ℃, is completely melted into milk white liquid at 100.6 ℃, and starts to bubble at 106.3 ℃ and gradually becomes colorless transparent liquid.
White solid,4.38g,overall yield 83.5％；1H NMR(400MHz,CD3CN)δ10.31(s,2H),7.81 (d,J＝2.4Hz,1H),7.57(d,J＝2.4Hz,1H),2.93(s,3H)；13C NMR(100MHz,CD3CN)δ151.8, 122.9,122.1,14.0；19F NMR(376MHz,CD3CN)δ61.6(s,1F)；HRMS(DART,m/z):Calcd. for C4H6O2N2FS:165.0129[M]+,Found:165.0130；HRMS(DART,m/z):Calcd.for HO4S: 96.9601[M]-,Found:96.9602.
Example 93
Preparation of 1- (fluorosulfonyl) -3-methyl-1H-imidazole fluorosulfonate
Preparation of Scheme 931- (fluorosulfonyl) -3-methyl-1H-imidazole fluorosulfonate
To a suspension of sodium carbonate (5.31g,50mmol) in acetonitrile (20mL) at room temperature was added imidazole [ compound 5]](1.36g,20mmol), the reaction system was pumped to negative pressure by a water pump, and sulfuryl fluoride gas [ Compound 2] was introduced into the reaction system through a balloon](0.6L, 24mmol), stirring overnight, TLC (petroleum ether: ethyl acetate 10:1, product R)f0.48), the reaction was completed, the reaction solution was filtered through silica gel (10 to 40 mesh), the cake was washed with dichloromethane (40mL), the filtrate was extracted with distilled water (100mL × 3), the aqueous phases were combined and back-extracted with dichloromethane (40mL), the organic phase was combined and washed with saturated brine (40mL), dried over anhydrous sodium sulfate, the filtrate was concentrated by a rotary evaporator (1H-imidazole-1-sulfonyl fluoride has a low boiling point, the temperature during concentration was controlled to 20 ℃ or less, and the pressure was controlled to 140torr or more), to obtain 1H-imidazole-1-fluorosulfonyl [ compound 6] as a product]5.79g of a mixed solution of methylene chloride and acetonitrile was quantified using p-toluenesulfonyl fluoride, and the product was 2.49g, i.e., yield was 83%. Adding dichloromethane (16mL) into the prepared mixed solution under the protection of nitrogen, cooling to 0 ℃ in an ice bath, slowly adding methyl fluorosulfonate (1.35mL and 16.6mmol) into the mixed solution by using a syringe under the stirring state, removing the ice bath after the dropwise addition is finished, reacting at room temperature for 2 hours, detecting the completion of the reaction by LC-MS, concentrating the reaction solution by using a rotary evaporator to obtain viscous oily matter, adding methyl tert-butyl ether (20mL), stirring to separate out a solid, pouring out the supernatant, washing the solid by using methyl tert-butyl ether (20mL multiplied by 2), and pumping out the solvent by using an oil pump to obtain white oilSolid 1- (fluorosulfonyl) -3-methyl-1H-imidazole fluorosulfonate [ compound 187]] (4.33g,98.7％；overall yield 81.9％)(Scheme 93)。
White solid,m.p.169-173℃,4.33g,over yield 81.9％；1H NMR(400MHz,CD3CN)δ 9.50(s,1H),8.02(s,1H),7.72(s,1H),4.01(s,3H)；13C NMR(100MHz,CD3CN)δ141.3, 127.7,122.4,38.6；19F NMR(376MHz,CD3CN)δ61.2(s,1F),38.3(s,1F)；HRMS(DART, m/z):Calcd.for C4H6O2N2FS:165.0129[M]+,Found:165.0130；HRMS(DART,m/z):Calcd. for O3FS:98.9558[M]-,Found:98.9562.
Example 94
Preparation of 1- (fluorosulfonyl) -2-isopropyl-3-methyl-1H-imidazole trifluoromethanesulfonate
Preparation of Scheme 941- (fluorosulfonyl) -2-isopropyl-3-methyl-1H-imidazole trifluoromethanesulfonate
Adding 2-isopropylimidazo [ compound 12] (2.21g,20mmol) to a suspension of sodium carbonate (5.30g,50mmol) in acetonitrile (20mL) at room temperature, pumping the reaction system to negative pressure with a water pump, introducing sulfuryl fluoride gas [ compound 2] (0.8L,32mmol) with an air balloon, stirring overnight, detecting the reaction by LC-MS, filtering the reaction mixture with silica gel (10-40 mesh), washing the cake with ethyl acetate (40mL), washing the organic phase with distilled water (100 mL. times.3), combining the aqueous phases, back-extracting with ethyl acetate (40mL), combining the organic phases, washing with saturated saline (40mL), drying over anhydrous sodium sulfate, filtering with filter paper, concentrating the filtrate by a rotary evaporator, purifying by column chromatography (silica gel 300 mesh 400, petroleum ether: dichloromethane: 5:1 pale yellow) to obtain 2-isopropyl-1-H-imidazole-1-fluorosulfonyl [ compound 13] (583mg, 15%).
Pale yellow oil,583mg,15％yield；1HNMR(400MHz,CDCl3)δ7.32(d,J＝1.8Hz,1H), 7.03(d,J＝1.8Hz,1H),3.47(sept,J＝6.8Hz,1H),1.38(d,J＝6.8Hz,6H)；13C NMR(100 MHz,CDCl3)δ155.8,128.9(d,J＝1.9Hz),119.8,27.7,21.7；19F NMR(376MHz,CDCl3)δ 58.9(s,1F)；HRMS(DART,m/z):Calcd.for C6H10O2N2FS:193.0442[M+H]+,Found: 193.0441.
To 2-isopropyl-1-H-imidazole-1-sulfonyl fluoride [ compound 13] (519mg,2.7 mmol) prepared above was added dichloromethane (2.7mL) under nitrogen protection, cooled to 0 ℃ in an ice bath, slowly adding methyl trifluoromethanesulfonate (305. mu.L, 2.7mmol) by using a syringe under the stirring state, removing the ice bath after the dropwise addition is finished, reacting at room temperature for 8 hours, the reaction was followed by TLC, the reaction solution was concentrated by rotary evaporator, and methyl t-butyl ether (20mL) was added and stirred to precipitate a solid, the supernatant was decanted, and the solid was washed with methyl t-butyl ether (20 mL. times.3) and the solvent was pumped off by an oil pump to give 1- (fluorosulfonyl) -2-isopropyl-3-methyl-1H-imidazole trifluoromethanesulfonate [ compound 14] (646mg, 67%) (Scheme 94) as a white solid.
White solid,m.p.77-80℃,646mg,67％yield；1HNMR(400MHz,CD3CN)δ7.85(d,J ＝2.6Hz,1H),7.54(d,J＝2.6Hz,1H),3.94(m,4H),1.52(d,J＝7.2Hz,6H)；13C NMR(100 MHz,CD3CN)δ155.5,126.5,123.1,122.0(q,J＝318Hz),39.1,27.8,18.2；19F NMR(376 MHz,CD3CN)δ62.1(s,1F),-78.1(s,3F)；HRMS(DART,m/z):Calcd.for C7H12O2N2FS: 207.0598[M]+,Found:207.0600；HRMS(DART,m/z):Calcd.for CO3F3S:148.9526[M]-, Found:148.9525.
Example 95
Preparation of 1- (fluorosulfonyl) -3-methyl-1H-benzimidazole trifluoromethanesulfonate
Preparation of Scheme 951- (fluorosulfonyl) -3-methyl-1H-benzimidazole trifluoromethanesulfonate
Benzimidazole [ compound 188] (2.37g,320mmol) was added to a suspension of sodium carbonate (5.31g,50mmol) in acetonitrile (20mL) at room temperature, the reaction system was pumped to a negative pressure with a water pump, sulfuryl fluoride gas [ compound 2] (0.8L,32mmol) was introduced with a balloon, the mixture was stirred overnight, the reaction was detected by LC-MS, the reaction solution was filtered with silica gel (10-40 mesh), the cake was washed with ethyl acetate (40mL), the organic phase was washed with distilled water (100mL × 3), the aqueous phase was combined and back-extracted with ethyl acetate (40mL), the organic phase was combined and washed with saturated saline (40mL), dried over anhydrous sodium sulfate, filtered through a filter paper, the filtrate was concentrated by a rotary evaporator, purified by column chromatography (silica gel 300-, 66%).
White solid,m.p.40-42℃,2.64g,66％yield；1H NMR(400MHz,CDCl3)δ8.27(s,1H), 7.90-7.80(m,2H),7.55-7.48(m,2H)；13C NMR(100MHz,CDCl3)δ143.4(d,J＝1.7Hz), 140.3(d,J＝1.5Hz),130.5,126.9,126.3,121.8,112.6；19F NMR(376MHz,CDCl3)δ56.4(s)； HRMS(DART,m/z):Calcd.for C7H6O2N2FS:201.0129[M+H]+,Found:201.0128.
To 1H-benzimidazole-1-sulfonyl fluoride [ compound 189] prepared above (2.57g,12.8mmol) was added dichloromethane (13mL) under nitrogen protection, cooled to 0 ℃ in an ice bath, slowly adding methyl trifluoromethanesulfonate (1.45mL,12.8mmol) by using a syringe under the stirring state, removing the ice bath after the dropwise addition is finished, reacting at room temperature for 6 hours, the reaction was followed by TLC, the reaction solution was concentrated to a white solid by rotary evaporator, the solid was dissolved with acetonitrile (4mL), methyl tert-butyl ether (40mL) was added and stirred to precipitate a solid, the supernatant was decanted, the solid was washed with methyl tert-butyl ether (20mL × 3), and the solvent was pumped off by an oil pump to give 1- (fluorosulfonyl) -3-methyl-1H-benzimidazole trifluoromethanesulfonate [ compound 190] (3.24g, 69%) (Scheme 95) as a white solid.
White solid,m.p.121-125℃,3.24g,69％yield；1HNMR(400MHz,CD3CN)δ9.91(s, 1H),8.11-8.05(m,2H),7.98-7.90(m,2H),4.25(s,3H)；13C NMR(100MHz,CD3CN)δ145.8, 133.3,131.5,130.4,129.3,121.8(q,J＝318Hz),116.2,115.0,36.1；19F NMR(376MHz, CD3CN)δ59.8(s,1F),-78.1(s,3F)；HRMS(DART,m/z):Calcd.for C8H10O3N2FS:233.0391 [M+H2O]+,Found:233.0392；HRMS(DART,m/z):Calcd.for CO3F3S:148.9526[M]-,Found: 148.9525.
Example 96
Preparation of anilinesulfonyl fluorides
Preparation of Scheme 96 anilinesulfonyl fluoride
1- (fluorosulfonyl) -2, 3-dimethyl-1H-imidazole trifluoromethanesulfonate [ compound 4] (3.61g,1mmol) was suspended in dichloromethane (50mL), aniline [ compound 191] (932mg,10mmol) was added under ice-cooling, the ice-cooling was removed after completion, the reaction was allowed to react at room temperature for 1 hour, LC-MS showed completion of the reaction, the reaction mixture was diluted with dichloromethane (100), washed with 0.1M hydrochloric acid (100 mL. times.3) and saturated brine (50 mL. times.2), dried over anhydrous sodium sulfate, filtered through filter paper, the filtrate was concentrated by a rotary evaporator, and the solvent was pumped off by an oil pump to obtain anilinesulfonyl fluoride [ compound 192] (1.55g, 88%) as a yellow oily substance (Scheme 96).
Yellow solid,1.55g,88％yield；1H NMR(400MHz,CD3CN)δ8.85(br,1H),7.44(m, 2H),7.33(m,3H)；13C NMR(101MHz,CD3CN)δ135.6(d,J＝2.7Hz),130.7,128.1,123.9(d, J＝1.8Hz)；19F NMR(376MHz,CD3CN)δ50.1(s).HRMS(DART,m/z):calcd for C6H5NO2FS:174.0031[M-H]-,found:174.0029.
Example 97
Preparation of 4-hydroxyanilino sulfonyl fluoride
Preparation of Scheme 974-hydroxyanilino sulfonyl fluoride
1- (fluorosulfonyl) -2, 3-dimethyl-1H-imidazole trifluoromethanesulfonate [ compound 4] (361mg,1.1mmol) was suspended in dichloromethane (10mL), and after completion of the reaction, 4-aminophenol [ compound 193] (109mg,1mmol) was added under ice-cooling, the ice-cooling was removed, the reaction was allowed to proceed at room temperature for 4 hours, and after completion of the reaction was detected by LC-MS, the reaction mixture was diluted with ethyl acetate (20mL), washed with 0.1M hydrochloric acid (20 mL. times.3) and saturated saline (20 mL. times.2), dried over anhydrous sodium sulfate, filtered through filter paper, and the filtrate was concentrated by a rotary evaporator, and the solvent was pumped off by an oil pump to obtain 4-hydroxyanilino sulfonyl fluoride [ compound 194] (174mg, 891%) (Scheme 97) as a brown oil.
Brown oil,174mg,91％yield；1H NMR(400MHz,CDCl3)δ7.21-7.17(m,2H),6.89(br, 1H),6.86-6.82(m,2H),6.53(br,1H)；13C NMR(100MHz,CD3CN)δ157.6,127.8(d,J＝1.9 Hz),126.9(d,J＝2.7Hz),117.1；19F NMR(376MHz,CDCl3)δ48.7(s,1F).HRMS(DART, m/z):calcd for C6H5FNO2S:189.9980[M-H]-,found:189.9977.
Example 98
Preparation of N-phenyl bis (fluorosulfonyl) imide
Preparation of Scheme 98N-phenyl bis (fluorosulfonyl) imide
Reacting aniline [ compound 191]](460. mu.L, 5.0mmol) in acetonitrile (20mL) and 1- (fluorosulfonyl) -2, 3-dimethyl-1H-imidazole trifluoromethanesulfonate [ Compound 4] added under ice-bath](4.27g,13mmol), stirring for 10min, triethylamine (360 μ L,2.6mmol) was added, the ice bath was removed after completion, the reaction was carried out at room temperature for 1h, TLC (petroleum ether: ethyl acetate ═ 9:1, product Rf= 0.65), the reaction solution was concentrated by a rotary evaporator, ethyl acetate (25mL) was added, the organic phase was washed with 0.1M hydrochloric acid (30mL × 3), deionized water (40mL × 2) and saturated brine (40mL × 2), dried over anhydrous sodium sulfate, filtered through filter paper, the filtrate was concentrated by a rotary evaporator, and the solvent was pumped off by an oil pump to obtain N-phenylbis (fluorosulfonyl) imide [ compound 195] as a yellow solid](1.05g,81％)(Scheme 98)。
Yellow solid,m.p.41-43℃,1.05g,81％yield；1H NMR(400MHz,CD3CN)δ7.72-7.62 (m)；13C NMR(101MHz,CD3CN)δ134.1(t,J＝1.8Hz),133.7,131.9,130.3(t,J＝1.2Hz)；19F NMR(376MHz,CD3CN)δ56.9(s)；HRMS(DART,m/z):calcd for C6H9F2N2O4S2: 274.9966[M+NH4]+,found:274.9965.
Example 99
Preparation of N- (3, 4-methylenedioxy) phenyl bis (fluorosulfonyl) imide
Preparation of Scheme 99N- (3, 4-methylenedioxy) phenyl bis (fluorosulfonyl) imide
3, 4-methylenedioxyaniline [ compound 196] (137mg,1.0mmol) was dissolved in acetonitrile (5mL), 1- (fluorosulfonyl) -2, 3-dimethyl-1H-imidazole trifluoromethanesulfonate [ compound 4] (820mg,2.5mmol) was added under ice-bath, triethylamine (69 μ L,0.5mmol) was added after stirring for 10 minutes, the ice-bath was removed after completion, reaction was carried out at room temperature for 1 hour, LC-MS detection was completed, and purification was carried out by column chromatography (silica gel 300 and 400 mesh, petroleum ether: dichloromethane ═ 6:1) to obtain N- (3, 4-methylenedioxy) phenyl bis (fluorosulfonyl) imide [ compound 197] (259mg, 86%) as a yellow solid (Scheme 99).
Yellow solid,m.p.49-51℃,259mg,86％yield；1H NMR(400MHz,CDCl3)δ7.01(m, 1H),6.90(m,2H),6.11(s,2H)；13C NMR(101MHz,CDCl3)δ151.1,149.3,125.7,124.0,109.6, 109.3,103.0；19F NMR(376MHz,CDCl3)δ55.2(s).HRMS(DART,m/z):calcd for C7H4NO6F2S2:299.9443[M-H]-,found:299.9451.
Example 100
Preparation of N- (4-ethynyl) phenyl bis (fluorosulfonyl) imide
Preparation of Scheme 100N- (4-ethynyl) phenyl bis (fluorosulfonyl) imide
4-ethynylaniline [ compound 198] (117mg,1.0mmol) was dissolved in acetonitrile (5mL), 1- (fluorosulfonyl) -2, 3-dimethyl-1H-imidazole trifluoromethanesulfonate [ compound 4] (821mg,2.5mmol) was added under ice-cooling, triethylamine (69 μ L,0.5mmol) was added after stirring for 10 minutes, the ice-cooling was removed after completion, the reaction was carried out at room temperature for 4 hours, LC-MS detection was completed, and purification was carried out by column chromatography (silica gel 300-400 mesh, petroleum ether: dichloromethane ═ 4:1) to obtain N- (4-ethynyl) phenylbis (fluorosulfonyl) imide [ compound 199] (203mg, 72%) as a pale yellow solid (Scheme 100).
Pale yellow solid,m.p.53-56℃,203mg,72％yield；1H NMR(400MHz,CDCl3)δ7.66 (m,2H),7.45(m,2H),3.27(s,1H)；13C NMR(101MHz,CDCl3)δ134.4,132.8(t,J＝1.8Hz), 129.3(t,J＝1.4Hz),127.0,81.5,81.3；19F NMR(376MHz,CDCl3)δ56.2(s).HRMS(DART, m/z):calcd for C8H9N2O4F2S2:298.9966[M+NH4]+,found:298.9965.
Example 101
Preparation of N-3-fluorophenyl bis (fluorosulfonyl) imide
Preparation of Scheme 101N-3-fluorophenyl bis (fluorosulfonyl) imide
Dissolving 3-fluoroaniline [ compound 198] (111mg,1.0mmol) in acetonitrile (5mL), adding 1- (fluorosulfonyl) -2, 3-dimethyl-1H-imidazole trifluoromethanesulfonate [ compound 4] (821mg,2.5mmol) under ice bath, stirring for 10 minutes, adding triethylamine (69 μ L,0.5mmol), removing the ice bath after the stirring is finished, reacting at room temperature for 1 hour, detecting by LC-MS, and purifying by column chromatography (silica gel 300-400 mesh, petroleum ether: dichloromethane ═ 4:1) to obtain N-3-fluorophenylbis (fluorosulfonyl) imide [ compound 201] (177mg, 64%) as a colorless oily liquid (Scheme 101).
Colorless oil,177mg,64％yield；1H NMR(400MHz,CD3CN)δ7.67(m,1H),7.56(m, 2H),7.48(m,1H)；13C NMR(101MHz,CDCl3)δ163.0(d,J＝251.1Hz),133.8(d,J＝9.9Hz), 132.0(d,J＝9.0Hz),125.3(d,J＝3.6Hz),120.0(d,J＝20.5Hz),117.2(d,J＝24.0Hz)；19F NMR(376MHz,CD3CN)δ57.3(s,2F),-108.8(m,1H).HRMS(DART,m/z):calcd for C6H8N2O4F3S2:292.9872[M+NH4]+,found:292.9871.
Example 102
Preparation of N- (2, 6-diisopropyl) phenyl bis (fluorosulfonyl) imide
Preparation of Scheme 102N- (2, 6-diisopropyl) phenyl bis (fluorosulfonyl) imide
2, 6-diisopropylaniline [ compound 202] (177mg,1.0mmol) was dissolved in acetonitrile (5mL), 1- (fluorosulfonyl) -2, 3-dimethyl-1H-imidazole trifluoromethanesulfonate [ compound 4] (821mg,2.5mmol) was added under ice-cooling, triethylamine (69 μ L,0.5mmol) was added after stirring for 10 minutes, the ice-cooling was removed after completion, the reaction was carried out at room temperature for 12 hours, LC-MS detection was completed, and purification was carried out by column chromatography (silica gel 300-400 mesh, petroleum ether: dichloromethane ═ 9:1) to obtain N- (2, 6-diisopropyl) phenylbis (fluorosulfonyl) imide [ compound 203] (180mg, 53%) as a colorless oily liquid (Scheme 102).
White solid,m.p.110-114℃,180mg,53％yield；1H NMR(400MHz,CDCl3)δ7.51(t, J＝7.8Hz,1H),7.30(d,J＝7.8Hz,2H),3.13(sept,J＝6.8Hz,2H),1.28(d,J＝6.8Hz,12H)；13C NMR(101MHz,CDCl3)δ149.1,132.7,129.1,126.0,29.5,24.0；19F NMR(376MHz, CDCl3)δ55.2(s)；HRMS(DART,m/z):calcd for C12H21N2O4F2S2:359.0905[M+NH4]+,found: 359.0904.
Example 103
Preparation of N- (2-phenoxy) ethyl bis (fluorosulfonyl) imide
Preparation of Scheme 103N- (2-phenoxy) ethyl bis (fluorosulfonyl) imide
2-Phenoxyethylamine [ compound 204] (137mg,1.0mmol) was dissolved in acetonitrile (5mL), 1- (fluorosulfonyl) -2, 3-dimethyl-1H-imidazole trifluoromethanesulfonate [ compound 4] (821mg,2.5mmol) was added thereto in ice bath, and after stirring for 10 minutes, triethylamine (69. mu.L, 0.5mmol) was added thereto, and after completion of the addition, the ice bath was removed and the reaction was allowed to proceed at room temperature for 1 hour, after the reaction was detected by LC-MS, the reaction mixture was diluted with ethyl acetate (20mL), washed with deionized water (20 mL. times.3) and saturated brine (20 mL. times.2), dried over anhydrous sodium sulfate, filtered through filter paper, the filtrate was concentrated by a rotary evaporator, and the solvent was drained by an oil pump to obtain N- (2-phenoxy) ethylbis (fluorosulfonyl) imide [ compound 201] (291mg, 96%) (Scheme 103) as a yellow oily liquid.
Yellow oil,291mg,96％yield；1H NMR(400MHz,CDCl3)δ7.31(m,2H),7.02(m,1H), 6.90(m,2H),4.42(t,J＝5.1Hz,2H),4.26(t,J＝5.1Hz,2H)；13C NMR(101MHz,CDCl3)δ 157.7,129.8,122.1,114.6,64.1,54.0；19F NMR(376MHz,CDCl3)δ58.4(s)；HRMS(DART, m/z):calcd for C8H9NO3F2S2:300.9885[M]+,found:300.9884.
Example 104
Preparation of N-phenyl bis (fluorosulfonyl) imide
Preparation of Scheme 104N-phenylbis (fluorosulfonyl) imide
Anilinesulfonyl fluoride [ compound 192] (175mg,1.0mmol) was dissolved in acetonitrile (5mL), 1- (fluorosulfonyl) -2, 3-dimethyl-1H-imidazole trifluoromethanesulfonate [ compound 4] (492mg,1.5mmol), triethylamine (360. mu.L, 2.6mmol) were added under ice-cooling, the ice-cooling was removed after completion, the reaction was carried out at room temperature for 1 hour, LC-MS detection showed completion of the reaction, the reaction solution was diluted with ethyl acetate (20mL), washed with deionized water (20 mL. times.3) and saturated saline (20 mL. times.2), dried over anhydrous sodium sulfate, filtered through filter paper, the filtrate was concentrated by a rotary evaporator, and the solvent was pumped off by an oil pump to give N-phenylbis (fluorosulfonyl) imide [ compound ] (195mg, 82%) (Scheme 104) as a pale yellow solid.
Pale yellow solid,m.p.41-43℃,212mg,82％yield；1H NMR(400MHz,CD3CN)δ 7.72-7.62(m)；13C NMR(101MHz,CD3CN)δ134.1(t,J＝1.8Hz),133.7,131.9,130.3(t,J＝ 1.2Hz)；19F NMR(376MHz,CD3CN)δ56.9(s).
Example 105
Preparation of benzenesulfonic acid isopropyl benzylamide
Preparation of Scheme 105 benzenesulfonic acid isopropyl benzyl amide
N-benzyl isopropylamine [ compound 108] (224mg,1.5mmol) was dissolved in acetonitrile (5mL) at room temperature, triethylamine (208. mu.L, 1.5mmol) and anilinesulfonyl fluoride [ compound 192] (175mg,1.0mmol) were added, and after completion, the reaction mixture was heated to 80 ℃ in an oil bath, reacted for 2 hours, and LC-MS detected that the reaction was completed, the reaction mixture was returned to room temperature, diluted with ethyl acetate (20mL), washed with 1M hydrochloric acid (20 mL. times.3) and saturated saline (20 mL. times.2), dried over anhydrous sodium sulfate, filtered through filter paper, the filtrate was concentrated by a rotary evaporator, and the solvent was pumped off by an oil pump to give benzenesulfonic acid isopropylacrylamide [ compound 206] (271mg, 89%) (Scheme 105) as a white solid.
White solid,m.p.91-95℃,271mg,89％yield；1H NMR(400MHz,CD3CN)δ7.67(br, 1H),7.33-7.09(m,10H),4.35(s,2H),4.00(sept,J＝6.7Hz,1H),0.97(d,J＝6.8Hz,6H).13C NMR(101MHz,CD3CN)δ140.2,139.1,130.1,129.1,128.5,128.0,124.8,120.6,51.5,48.2, 21.3.HRMS(DART,m/z):calcd for C16H21O2N2S:305.1318[M+H]+,found:305.1315.
Example 106
Fluorosulfonyl azide (FSO)2N3) Preparation of
Under ice bath, aqueous sodium azide (0.25M, 20 ml; containing 5mmol of NaN)3) To a mixture with methyl tert-butyl ether (20ml) was added a solution of 1- (fluorosulfonyl) -2, 3-dimethyl-1H-imidazole trifluoromethanesulfonate in acetonitrile (6mmol 9,1ml MeCN). The reaction system was stirred for 10 minutes under ice bath, and then the reaction solution was allowed to stand at room temperature (25 ℃) for 5 minutes. Removing the water phase in the reaction system to obtain an organic phase, namely the fluorosulfonyl azide (FSO)2N3) Solution, yield 92% (by passing over19Signal integration in F NMR, relative to moles of sodium azide used). The solution can be directly used for diazo transfer reaction of primary amino compounds without further purification.
Example 107
Preparation of 4-benzylpiperidine-1-sulfonyl fluoride
Preparation of Scheme 1074-benzylpiperidine-1-sulfonyl fluoride
4-benzylpiperidine [ compound 112] (175mg,1mmol) was dissolved in acetonitrile (2mL) at room temperature, 1- (fluorosulfonyl) -2, 3-dimethyl-1H-imidazole trifluoromethanesulfonate [ compound 4] (329mg,1mmol) was added to the solution, the reaction was carried out for 1 hour, LC-MS detection of completion of the reaction was carried out, water (10mL) was added to the reaction solution, ethyl acetate (10 mL. times.3) was extracted, the organic phases were combined, washed with water (15mL) and saturated brine (15mL), dried over anhydrous sodium sulfate, filtered through filter paper, the filtrate was concentrated by a rotary evaporator, and the solvent was removed by an oil pump to obtain 4-benzylpiperidine-1-sulfonylfluoride [ compound 113] (254mg, 99%) (Scheme 107) as a pale yellow solid.
Pale yellow solid, m.p.58-61 ℃,254mg, 99% yield;1H NMR(400MHz,CDCl3)δ7.30-7.11 (m,5H),3.90-3.85(m,2H),2.94-2.85(m,2H),2.56(d,J＝6.8Hz,2H),1.75-1.62(m,3H),1.35 (dq,J＝4Hz,J＝11.6Hz,2H)；13C NMR(100MHz,CDCl3)δ139.4,129.1,128.5,126.3,47.6, 42.6,37.0,30.7；19F NMR(376MHz,CDCl3)δ39.6(s,1F)；LC-MS(tR):1.71min；ESI-MS (m/z):258[MH]+.
example 108
Preparation of 4-benzylpiperidine-1-sulfonyl fluoride
Preparation of Scheme 1084-benzylpiperidine-1-sulfonyl fluoride
4-benzylpiperidine [ compound 112] (175mg,1mmol) was dissolved in acetonitrile (2mL) at room temperature, 1- (fluorosulfonyl) -2, 3-dimethyl-1H-imidazole trifluoromethanesulfonate [ compound 7] (314mg,1mmol) was added to the solution, the reaction was carried out for 1 hour, LC-MS detection of the completion of the reaction was carried out, water (10mL) was added to the reaction solution, ethyl acetate (10 mL. times.3) was extracted, the organic phases were combined, washed with water (15mL) and saturated brine (15mL), dried over anhydrous sodium sulfate, filtered through filter paper, the filtrate was concentrated by a rotary evaporator, and the solvent was removed by an oil pump to obtain 4-benzylpiperidine-1-sulfonylfluoride [ compound 113] (238mg, 92%) (Scheme 108) as a pale yellow solid.
Pale yellow solid, m.p.58-61 ℃,238mg, 92% yield;1H NMR(400MHz,CDCl3)δ7.30-7.11 (m,5H),3.90-3.85(m,2H),2.94-2.85(m,2H),2.56(d,J＝6.8Hz,2H),1.75-1.62(m,3H),1.35 (dq,J＝4Hz,J＝11.6Hz,2H)；19F NMR(376MHz,CDCl3)δ39.6(s,1F)；LC-MS(tR):1.71 min；ESI-MS(m/z):258[MH]+.
example 109
Preparation of 4-benzylpiperidine-1-sulfonyl fluoride
Preparation of Scheme 1094-benzylpiperidine-1-sulfonyl fluoride
At room temperature, 4-benzylpiperidine [ compound 112] (175mg,1mmol) was dissolved in acetonitrile (2mL), 1- (fluorosulfonyl) -2, 3-dimethyl-1H-imidazole trifluoromethanesulfonate [ compound 14] (357mg,1mmol) was added and reacted for 1 hour, LC-MS detected that the reaction was completed, water (10mL) was added to the reaction solution, ethyl acetate (10mL × 3) was extracted, the organic phases were combined and washed with water (15mL) and saturated saline (15mL), dried over anhydrous sodium sulfate, filtered through filter paper, the filtrate was concentrated by a rotary evaporator and purified by column chromatography (silica gel 300-.
Pale yellow solid, m.p.58-61 ℃,215mg, 84% yield;1H NMR(400MHz,CDCl3)δ7.30-7.11 (m,5H),3.90-3.85(m,2H),2.94-2.85(m,2H),2.56(d,J＝6.8Hz,2H),1.75-1.62(m,3H),1.35 (dq,J＝4Hz,J＝11.6Hz,2H)；19F NMR(376MHz,CDCl3)δ39.6(s,1F)；LC-MS(tR):1.71 min；ESI-MS(m/z):258[MH]+.
example 111
Preparation of 4-benzylpiperidine-1-sulfonyl fluoride
Preparation of Scheme 1114-benzylpiperidine-1-sulfonyl fluoride
Dissolving 4-benzylpiperidine [ compound 112] (175mg,1mmol) in acetonitrile (2mL) at room temperature, adding 1- (fluorosulfonyl) -2, 3-dimethyl-1H-imidazole trifluoromethanesulfonate [ compound 17] (379mg,1mmol), reacting for 1 hour, detecting the reaction completion by LC-MS, adding water (10mL) to the reaction solution, extracting with ethyl acetate (10mL × 3), combining the organic phases, washing with water (15mL) and saturated saline (15mL), drying over anhydrous sodium sulfate, filtering with filter paper, concentrating the filtrate by a rotary evaporator, and purifying by column chromatography (silica gel 300-400 mesh, petroleum ether: ethyl acetate ═ 20:1) to obtain a pale yellow solid 4-benzylpiperidine-1-sulfonyl fluoride [ compound 113] (205mg, 80%) (Scheme 111).
Pale yellow solid, m.p.58-61 ℃,205mg, 80% yield;1H NMR(400MHz,CDCl3)δ7.30-7.11 (m,5H),3.90-3.85(m,2H),2.94-2.85(m,2H),2.56(d,J＝6.8Hz,2H),1.75-1.62(m,3H),1.35 (dq,J＝4Hz,J＝11.6Hz,2H)；19F NMR(376MHz,CDCl3)δ39.6(s,1F)；LC-MS(tR):1.71 min；ESI-MS(m/z):258[MH]+.
example 112
Preparation of 4-benzylpiperidine-1-sulfonyl fluoride
Preparation of Scheme 1124-benzylpiperidine-1-sulfonyl fluoride
Dissolving 4-benzylpiperidine [ compound 112] (175mg,1mmol) in acetonitrile (2mL) at room temperature, adding 1- (fluorosulfonyl) -2, 3-dimethyl-1H-imidazole trifluoromethanesulfonate [ compound 23] (357mg,1mmol), reacting for 1 hour, detecting the completion of the reaction by LC-MS, adding water (10mL) to the reaction solution, extracting with ethyl acetate (10mL × 3), combining the organic phases, washing with water (15mL) and saturated saline (15mL), drying over anhydrous sodium sulfate, filtering with filter paper, concentrating the filtrate by a rotary evaporator, and purifying by column chromatography (silica gel 300-400 mesh, petroleum ether: ethyl acetate ═ 20:1) to obtain a pale yellow solid 4-benzylpiperidine-1-sulfonylfluoride [ compound 113] (212mg, 82%) (Scheme 112).
Pale yellow solid, m.p.58-61 ℃,212mg, 82% yield;1H NMR(400MHz,CDCl3)δ7.30-7.11 (m,5H),3.90-3.85(m,2H),2.94-2.85(m,2H),2.56(d,J＝6.8Hz,2H),1.75-1.62(m,3H),1.35 (dq,J＝4Hz,J＝11.6Hz,2H)；19F NMR(376MHz,CDCl3)δ39.6(s,1F)；LC-MS(tR):1.71 min；ESI-MS(m/z):258[MH]+.
example 113
Preparation of 4-benzylpiperidine-1-sulfonyl fluoride
Preparation of Scheme 1134-benzylpiperidine-1-sulfonyl fluoride
4-benzylpiperidine [ compound 112] (175mg,1mmol) was dissolved in acetonitrile (2mL) at room temperature, 1- (fluorosulfonyl) -2, 3-dimethyl-1H-imidazole trifluoromethanesulfonate [ compound 185] (279mg,1mmol) was added and reacted for 1 hour, LC-MS detected that the reaction was completed, water (10mL) was added to the reaction solution, ethyl acetate (10 mL. times.3) was extracted, the organic phases were combined and washed with water (15mL) and saturated brine (15mL), dried over anhydrous sodium sulfate, filtered through filter paper, the filtrate was concentrated by a rotary evaporator, and the solvent was pumped off by an oil pump to obtain 4-benzylpiperidine-1-sulfonylfluoride [ compound 113] (252mg, 98%) (Scheme 113) as a pale yellow solid.
Pale yellow solid, m.p.58-61 ℃,252mg, 98% yield;1H NMR(400MHz,CDCl3)δ7.30-7.11 (m,5H),3.90-3.85(m,2H),2.94-2.85(m,2H),2.56(d,J＝6.8Hz,2H),1.75-1.62(m,3H),1.35 (dq,J＝4Hz,J＝11.6Hz,2H)；19F NMR(376MHz,CDCl3)δ39.6(s,1F)；LC-MS(tR):1.71 min；ESI-MS(m/z):258[MH]+.
example 114
Preparation of 4-benzylpiperidine-1-sulfonyl fluoride
Preparation of Scheme 1144-benzylpiperidine-1-sulfonyl fluoride
Dissolving 4-benzylpiperidine [ compound 112] (175mg,1mmol) in acetonitrile (2mL) at room temperature, adding 1- (fluorosulfonyl) -2, 3-dimethyl-1H-imidazole trifluoromethanesulfonate [ compound 187] (265mg,1mmol), reacting for 1 hour, detecting the completion of the reaction by LC-MS, adding water (10mL) to the reaction solution, extracting with ethyl acetate (10 mL. times.3), combining the organic phases, washing with water (15mL) and saturated saline (15mL), drying over anhydrous sodium sulfate, filtering with filter paper, concentrating the filtrate by a rotary evaporator, and draining off the solvent by an oil pump to obtain a pale yellow solid, 4-benzylpiperidine-1-sulfonylfluoride [ compound 113] (235mg, 91%) (Scheme 114).
Pale yellow solid, m.p.57-61 ℃,235mg, 91% yield;1H NMR(400MHz,CDCl3)δ7.30-7.11 (m,5H),3.90-3.85(m,2H),2.94-2.85(m,2H),2.56(d,J＝6.8Hz,2H),1.75-1.62(m,3H),1.35 (dq,J＝4Hz,J＝11.6Hz,2H)；19F NMR(376MHz,CDCl3)δ39.6(s,1F)；LC-MS(tR):1.71 min；ESI-MS(m/z):258[MH]+.
example 115
Preparation of 4-benzylpiperidine-1-sulfonyl fluoride
Preparation of Scheme 1154-benzylpiperidine-1-sulfonyl fluoride
At room temperature, 4-benzylpiperidine [ compound 112] (175mg,1mmol) was dissolved in acetonitrile (2mL), 1- (fluorosulfonyl) -2, 3-dimethyl-1H-imidazole trifluoromethanesulfonate [ compound 4] (329mg,1mmol) was added and reacted for 1 hour, LC-MS detection of completion of the reaction was performed, water (10mL) was added to the reaction solution, ethyl acetate (10mL × 3) was extracted, the organic phases were combined and washed with water (15mL) and saturated saline (15mL), dried over anhydrous sodium sulfate, filtered through filter paper, the filtrate was concentrated by a rotary evaporator and purified by column chromatography (silica gel 300-400 mesh, petroleum ether: ethyl acetate ═ 9:1) to obtain 4-benzylpiperidine-1-sulfonylfluoride [ compound 113] (196mg, 76%) (Scheme 115) as a pale yellow solid.
Pale yellow solid, m.p.58-61 ℃,196mg, 76% yield;1H NMR(400MHz,CDCl3)δ7.30-7.11 (m,5H),3.90-3.85(m,2H),2.94-2.85(m,2H),2.56(d,J＝6.8Hz,2H),1.75-1.62(m,3H),1.35 (dq,J＝4Hz,J＝11.6Hz,2H)；19F NMR(376MHz,CDCl3)δ39.6(s,1F)；LC-MS(tR):1.71 min；ESI-MS(m/z):258[MH]+.
example 116
Preparation of N-isopropylbenzylamine sulfonyl fluoride
Preparation of Scheme 116N-benzyl isopropylamine sulfonyl fluoride
N-benzyl isopropylamine [ compound 108] (149mg,1mmol) was dissolved in acetonitrile (2mL) at room temperature, 1- (fluorosulfonyl) -2, 3-dimethyl-1H-imidazole trifluoromethanesulfonate [ compound 4] (329mg,1mmol) was added and reacted for 1 hour, LC-MS detects completion of the reaction, water (10mL) was added to the reaction solution, ethyl acetate (10mL × 3) was extracted, the organic phases were combined and washed with water (15mL) and saturated brine (15mL), dried over anhydrous sodium sulfate, filtered through filter paper, the filtrate was concentrated by rotary evaporator, and the solvent was pumped off by an oil pump to obtain N-benzyl isopropylamine sulfonylfluoride [ compound 109] (198mg, 86%) as a yellow oil (Scheme 116).
Yellow oil, 198mg, 86% yield;1H NMR(400MHz,CDCl3)δ7.37-7.29(m,5H),4.49(s, 2H),4.07(sept,J＝6.8Hz,1H),1.23(d,J＝6.8Hz,6H)；13C NMR(100MHz,CDCl3)δ136.3 (d,J＝2.2Hz),128.8,128.1,127.6,53.5(d,J＝2.3Hz),49.7(d,J＝1.8Hz),20.6(d,J＝2.0Hz)；19F NMR(376MHz,CDCl3)δ50.6(s,1F).
example 117
Preparation of N-isopropylbenzylamine sulfonyl fluoride
Preparation of Scheme 117N-benzyl isopropylamine sulfonyl fluoride
N-benzyl isopropylamine [ compound 108] (149mg,1mmol) was dissolved in acetonitrile (2mL) at room temperature, 1- (fluorosulfonyl) -2, 3-dimethyl-1H-imidazole trifluoromethanesulfonate [ compound 7] (315mg,1mmol) was added and reacted for 1 hour, LC-MS detects that the reaction was completed, water (10mL) was added to the reaction solution, ethyl acetate (10mL × 3) was extracted, the organic phases were combined and washed with water (15mL) and saturated brine (15mL), dried over anhydrous sodium sulfate, filtered through filter paper, the filtrate was concentrated by rotary evaporator, and the solvent was pumped off by an oil pump to obtain N-benzyl isopropylamine sulfonylfluoride [ compound 109] (170mg, 74%) (Scheme 117) as a yellow oil.
Yellow oil, 170mg, 74% yield;1H NMR(400MHz,CDCl3)δ7.37-7.29(m,5H),4.49(s, 2H),4.07(sept,J＝6.8Hz,1H),1.23(d,J＝6.8Hz,6H)；19F NMR(376MHz,CDCl3)δ50.6 (s,1F).
example 118
Preparation of N-isopropylbenzylamine sulfonyl fluoride
Preparation of Scheme 118N-benzyl isopropylamine sulfonyl fluoride
N-benzyl isopropylamine [ compound 108] (149mg,1mmol) was dissolved in acetonitrile (3mL) at room temperature, 1- (fluorosulfonyl) -2, 3-dimethyl-1H-imidazole trifluoromethanesulfonate [ compound 185] (279mg,1mmol) was added and reacted for 1 hour, LC-MS detects completion of the reaction, water (10mL) was added to the reaction solution, ethyl acetate (10mL × 3) was extracted, the organic phases were combined and washed with water (15mL) and saturated brine (15mL), dried over anhydrous sodium sulfate, filtered through filter paper, the filtrate was concentrated by rotary evaporator, and the solvent was pumped off by an oil pump to obtain N-benzyl isopropylamine sulfonylfluoride [ compound 109] (195mg, 84%) (Scheme 118) as a yellow oil.
Yellow oil, 195mg, 84% yield;1H NMR(400MHz,CDCl3)δ7.37-7.29(m,5H),4.49(s, 2H),4.07(sept,J＝6.8Hz,1H),1.23(d,J＝6.8Hz,6H)；19F NMR(376MHz,CDCl3)δ50.6 (s,1F).
example 119
Preparation of N-isopropylbenzylamine sulfonyl fluoride
Preparation of Scheme 119N-benzyl isopropylamine sulfonyl fluoride
N-benzyl isopropylamine [ compound 108] (149mg,1mmol) was dissolved in acetonitrile (3mL) at room temperature, 1- (fluorosulfonyl) -2, 3-dimethyl-1H-imidazole trifluoromethanesulfonate [ compound 187] (265mg,1mmol) was added and reacted for 1 hour, LC-MS detects completion of the reaction, water (10mL) was added to the reaction solution, ethyl acetate (10mL × 3) was extracted, the organic phases were combined and washed with water (15mL) and saturated brine (15mL), dried over anhydrous sodium sulfate, filtered through filter paper, the filtrate was concentrated by rotary evaporator, and the solvent was pumped off by an oil pump to obtain N-benzyl isopropylamine sulfonyl fluoride [ compound 109] (186mg, 80%) (Scheme 119) as a yellow oil.
Yellow oil, 186mg, 80% yield;1H NMR(400MHz,CDCl3)δ7.37-7.29(m,5H),4.49(s, 2H),4.07(sept,J＝6.8Hz,1H),1.23(d,J＝6.8Hz,6H)；19F NMR(376MHz,CDCl3)δ50.6 (s,1F)。

Claims (17)

1. a fluorosulfonyl compound, comprising a cation represented by formula 1 and an anion:
wherein R is1、R2、R3And R4Each independently is hydrogen or C1-6Alkyl, or R3And R4And the carbon atoms therebetween together form a benzene ring.
2. The fluorosulfonyl compound of claim 1, consisting of said cation and said anion.
3. The fluorosulfonyl compound of claim 1 or 2,
when R is1Is C1-6When alkyl, said C1-6Alkyl is C1-4An alkyl group;
and/or when R2Is C1-6When alkyl, said C1-6Alkyl is C1-4An alkyl group;
and/or when R3Is C1-6When alkyl, said C1-6Alkyl is C1-4An alkyl group;
and/or when R4Is C1-6When alkyl, said C1-6Alkyl is C1-4An alkyl group.
4. The fluorosulfonyl compound of claim 3,
when R is1Is C1-6Alkyl radical, said C1-6Alkyl is C1-4When alkyl, said C1-4Alkyl is methyl, ethyl, isopropyl or butyl;
and/or when R2Is C1-6Alkyl radical, said C1-6Alkyl is C1-4When alkyl, said C1-4Alkyl is methyl or butyl;
and/or when R3Is C1-6Alkyl radical, said C1-6Alkyl is C1-4When alkyl, said C1-4Alkyl is methyl or butyl;
and/or when R4Is C1-6Alkyl radical, said C1-6Alkyl is C1-4When alkyl, said C1-4Alkyl is methyl or butyl.
5. The fluorosulfonyl compound of claim 1,
the cation is Preferably is
And/or, the anion is-R5Wherein R is5Is composed ofBF4Or PF6Preferably is
6. The fluorosulfonyl compound of claim 1, wherein said fluorosulfonyl compound is selected from the group consisting of:
7. a method for producing a fluorosulfonyl compound according to claim 1, comprising the steps of:
in a first organic solvent, addingAnd R2-anionic reaction, i.e. reaction.
8. The method for producing a fluorosulfonyl compound according to claim 7,
the anion is R5The anion formed;
and/or, the first organic solvent is selected from one or more of acetonitrile, dichloromethane, diethyl ether, tetrahydrofuran, 1, 2-dichloroethane, dimethyl sulfoxide, N-dimethylformamide, methyl tert-butyl ether and chloroform, preferably methyl tert-butyl ether;
and/or the temperature of the reaction is-15 ℃ to 20 ℃, preferably 0 ℃.
9. The method for producing a fluorosulfonyl compound according to claim 7 or 8, further comprising the steps of: in a second organic solvent in the presence of a base,and sulfuryl fluoride, thereby obtaining said
10. The method for producing a fluorosulfonyl compound according to claim 9,
the second organic solvent is one or more selected from acetonitrile, dichloromethane, ethyl acetate, benzene, toluene, acetone, 1, 4-dioxane, diethyl ether, tetrahydrofuran, 1, 2-dichloroethane, dimethyl sulfoxide, N-dimethylformamide, N-methylpyrrolidone, methyl tert-butyl ether and chloroform, preferably acetonitrile;
and/or, the base comprises an inorganic base and an organic base;
and/or the reaction is carried out at-20 ℃ to 35 ℃.
11. The method for producing a fluorosulfonyl compound according to claim 10,
the inorganic base is one or more selected from sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, sodium bicarbonate and potassium bicarbonate, preferably sodium carbonate; the organic base is selected from one or more of triethylamine, N-diisopropylethylamine, pyrrole and pyridine, preferably triethylamine;
and/or the reaction is carried out at 5 ℃ to 30 ℃.
12. Use of a fluorosulfonyl compound of claim 1 as a fluorosulfonyl reagent.
13. The application of claim 12, wherein the application comprises the steps of: reacting a substrate with the fluorine-containing sulfonyl compound;
wherein the substrate is a compound containing phenolic hydroxyl, primary amine or secondary amine.
14. The use according to claim 13, wherein the number of phenolic hydroxyl groups in the phenolic hydroxyl group-containing compound is one, two or three.
15. The use according to any one of claims 12 to 14,
when the substrate is a phenolic hydroxyl group-containing compound, the product obtained by the reaction is selected from the following compounds:
and/or, when the substrate is a primary amine, the reaction results in a product selected from the group consisting of:
and/or, when the substrate is a secondary amine, the product resulting from the reaction is selected from the group consisting of:
16. the use according to claim 13,
the reaction is carried out at 0-35 ℃, preferably at 5-30 ℃;
and/or the reaction time is 5min-6h, preferably 10min-4h, more preferably 1h or 2 h;
and/or the reaction is carried out in an organic solvent, wherein the organic solvent is acetonitrile, dichloromethane or ethyl acetate.
17. An intermediate of a fluorosulfonyl compound, having a structure represented by formula 2:
CN201810609858.6A 2017-11-22 2018-06-13 Fluorine-containing sulfonyl compound, intermediate, preparation method and application thereof Pending CN110590609A (en)

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