A 4-vinyl dihydrofuran-3,3(2h)-disulfonyl difluoride compound and preparation and application thereof

Abstract

The application relates to a 4-vinyl dihydrofuran-3,3(2H)-disulfonyl difluoride compound and preparation and application thereof, the compound has a structure as shown in formula 1: in the formula, R is selected from one of a methyl group, a methoxy group, a phenyl group, a fluorine atom, a chlorine atom, a bromine atom and a nitro group. Compared with the prior art, the preparation method is simple, raw materials are simple, can be popularized on a large scale, and has good development potential and application prospect in the biological medicine field.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of organic synthesis, and particularly relates to a 4-vinyl dihydrofuran-3,3(2H)-disulfonyl difluoride compound and preparation and application thereof. BACKGROUND

[0002] Furan compounds are an important skeleton, which are widely present in natural products and other molecules with biological activity. Such molecules have a broad spectrum of therapeutic applications, for example: HIV-1 protease inhibitors containing furan skeleton synthesis have excellent antiviral activity in the treatment of HIV / AIDS (doi:10.1021 / acs.jmedchem.5b01697.); furan ring ciprofloxacin derivatives with antibacterial and cytotoxic activity, which also contain a furan core skeleton (doi.org / 10.1080 / 00397911.2016.1234622); the core skeleton of gemcitabine is furan structure, which is an anticancer drug acting on various solid tumors, and has inhibitory effect on various solid tumors such as pancreatic cancer, non-small cell lung cancer, breast cancer and ovarian cancer, and is widely used in clinical treatment (doi.org / 10.1021 / mp300370t). However, there are few reports on the synthesis method of ethenyl dihydrofuran compounds and derivatives thereof in the existing literature.

[0003] Therefore, it is of great significance to develop a method for efficiently synthesizing ethenyl dihydrofuran compounds by palladium catalysis. The synthesis methods reported in the literature mainly include the following:

[0004] (1) In 2002, Zhang et al. synthesized (Z)-3-benzylidene-4-vinyltetrahydrofuran by using [Rh(cod)Cl]2 and (R)-BINAP as catalysts, silver hexafluoroantimonate as additive, and under nitrogen atmosphere (doi:10.1002 / 1521-3773(20020916)41:18<3457::AID-ANIE3457>3.0.CO;2-3.).

[0005] (2) In 2003, Zhang et al. synthesized (E)-3-benzylidene-4-vinyltetrahydrofuran by using (Z)-1-(but-2-yn-1-oxyl)-4-chlorobut-2-ene and phenylboronic acid as raw materials, and under the catalysis of tetrakis triphenylphosphine and hydrogen fluoride in toluene solvent (doi.org / 10.1021 / ol035304f).

[0006] (iii) In 2004, Coates group synthesized 4-benzyl-2-phenyl-3-vinyltetrahydrofuran in 76% yield from 6-benzyl-2,2-dimethyl-2,3,6,7-tetrahydro-1,2-oxepin and benzaldehyde as starting materials, via allylsiloxane / aldehyde condensation catalyzed by boron trifluoride etherate complex (doi.org / 10.1021 / jo048971a).

[0007] (iv) In 2017, Yoshikai et al. synthesized a series of alkenyltetrahydrofuran compounds in 63-88% yield from (E)-(3-((3-cyclopropylallyl)oxy)prop-1-yn-1-yl)benzene as starting material, via intramolecular allylic substitution catalyzed by cobalt bromide (doi.org / 10.1002 / anie.201803162).

[0008] In summary, the current one-step synthesis of vinyl dihydrofuran compounds only has the above methods, mainly intramolecular reaction, and the raw materials are not easy to obtain, the preparation process is complex, and the reaction system is complex. SUMMARY

[0009] The present application provides a 4-vinyl dihydrofuran-3,3(2H)-disulfonyl difluoride compound, which has the structure shown in formula 1:

[0010] The object of the present application can be achieved by the following technical solutions:

[0011] The present application provides a 4-vinyl dihydrofuran-3,3(2H)-disulfonyl difluoride compound, which has the structure shown in formula 1:

[0012]

[0013] In the formula, R is selected from one of methyl, methoxy, phenyl, fluorine atom, chlorine atom, bromine atom and nitro group.

[0014] The present application also provides a preparation method of 4-vinyl dihydrofuran-3,3(2H)-disulfonyl difluoride compound, which comprises the following steps:

[0015] The mixed substituted 1,3-butadiene-1,1-disulfonyl difluoride compound, ethylene oxide, a catalyst and a ligand are subjected to a [3+2] cycloaddition reaction in an organic solvent, and after filtration, extraction and purification through silica gel column chromatography, the 4-vinyl dihydrofuran-3,3(2H)-disulfonyl difluoride compound is obtained.

[0016] Further, the substituted 1,3-butadiene-1,1-disulfonyl difluoride compound has a structure as shown in formula 2:

[0017]

[0018] In the formula, R is selected from one of methyl, methoxy, phenyl, fluorine atom, chlorine atom, bromine atom and nitro group.

[0019] Further, the catalyst is tris(dibenzylideneacetone)dipalladium-chloroform adduct.

[0020] Further, the ligand is L2.

[0021] Further, the organic solvent is dichloromethane.

[0022] Further, the molar ratio of the substituted 1,3-butadiene-1,1-disulfonyl difluoride compound, ethylene oxide, catalyst and ligand is 1:(1-2):(0.01-0.04):(0.005-0.015).

[0023] Further, the specific conditions of the [3+2] cycloaddition reaction are as follows:

[0024] The reaction temperature is 20-40 DEG C, and the reaction time is 30-50 h.

[0025] Further, the filtration conditions are that the disappearance of the substituted 1,3-butadiene-1,1-disulfonyl difluoride compound, ethylene oxide, catalyst and ligand is monitored by TLC.

[0026] The application further provides a use of the 4-vinyl dihydrofuran-3,3(2H)-disulfonyl difluoride compound in an anticancer drug.

[0027] Compared with the prior art, the application has the following beneficial effects:

[0028] 1. The application uses a simple and easily available substituted 1,3-butadiene-1,1-disulfonyl difluoride compound as a raw material, and a cheap and easily available Pd2dba3.CHCl3 as a catalyst, and a series of 4-vinyl dihydrofuran-3,3(2H)-disulfonyl difluoride compounds are obtained through a [3+2] cycloaddition reaction.

[0029] 2、Compared with the prior art, the traditional method of ethylenyl dihydrofuran compounds is mainly intramolecular reaction, the application combines sulfonyl fluoride reagent with five-membered heterocyclic skeleton, uses simple and easily obtained substituted 1,3-butadiene-1,1-disulfonyl difluoride compound as raw material, and cheap and easily obtained Pd2dba3.CHCl3 as catalyst, and a series of 4-ethylenyl dihydrofuran-3,3(2H)-disulfonyl difluoride compounds are obtained through [3+2] cycloaddition reaction.

[0030] 3, The ring tension induced cycloaddition reaction has good reaction activity and excellent chemical and stereoselectivity, and the ethylenyl oxirane serves as a three-atom component, so that the five-membered heterocyclic skeleton can be constructed in a regioselective and stereoselective manner. BRIEF DESCRIPTION OF DRAWINGS

[0031] Figure 1 It is a preparation flowchart of 4-ethylenyl dihydrofuran-3,3(2H)-disulfonyl difluoride compounds of the application.

[0032] Figure 2 It is an H NMR spectrum in example 1. 1

[0033] Figure 3 It is an F NMR spectrum in example 1. 19

[0034] Figure 4 It is a C NMR spectrum in example 1. 13

[0035] Figure 5 It is an H NMR spectrum in example 2. 1

[0036] Figure 6 It is an F NMR spectrum in example 2. 19

[0037] Figure 7 It is a C NMR spectrum in example 2. 13

[0038] Figure 8 It is an H NMR spectrum in example 3. 1

[0039] Figure 9 It is an F NMR spectrum in example 3. 19

[0040] Figure 10 It is a C NMR spectrum in example 3. 13

[0041] Figure 11 ​​​​​​​​​as in Example 4 1 H NMR spectra.

[0042] Figure 12 as in Example 4 19 F NMR spectra.

[0043] Figure 13 as in Example 4 13 C NMR spectra. DETAILED DESCRIPTION

[0044] For the purposes of the present application, the following examples will be more fully described. The present application may, however, be carried out in many different forms without being limited to the embodiments described herein. Rather, these embodiments are provided so that this disclosure will be thorough and complete, and fully convey the scope of the application to those skilled in the art.

[0045] For the sake of brevity, the present application will only explicitly disclose some numerical ranges. However, any lower limit can be combined with any upper limit to form a range not explicitly recited; and any lower limit can be combined with other lower limits to form a range not explicitly recited, as can any upper limit with any other upper limit. In addition, even though not explicitly recited, every point or individual value within a range is to be included in the range. Thus, every point or individual value can serve as its own lower limit or upper limit to combine with every other point or individual value or to another lower limit or upper limit to form a range not explicitly recited.

[0046] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs. The terminology used in the description herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the application. It is to be understood that the use of "and / or" includes a combination of one or more of the associated listed items, "at least one of' means one or more, and "one or more" means two or more.

[0047] The following raw materials and suppliers are referred to in the detailed description and examples below.

[0048] Cinnamaldehyde (Adamas, RG, 99%);

[0049] (E)-3-(2-methoxyphenyl)propenal (Bide Pharmaceutica, RG, 99%);

[0050] (E)-3-(2-chlorophenyl)propenal (Bide Pharmaceutica, RG, 95%);

[0051] (E)-3-(2-bromophenyl)acrylaldehyde (Biotrend, RG, 97%);

[0052] (E)-3-(4-fluorophenyl)acrylaldehyde (Biotrend, RG, 95%);

[0053] (E)-3-(4-fluorophenyl)acrylaldehyde (Biotrend, RG, 95%);

[0054] (E)-3-(4-nitrophenyl)acrylaldehyde (Biotrend, RG, 98%);

[0055] (E)-3-([1,1'-biphenyl]-4-yl)acrylaldehyde (Biotrend RG, 98%);

[0056] Vinyl oxirane (Adamas, RG, 98%);

[0057] Tris(dibenzylideneacetone)dipalladium-chloroform adduct (Biotrend, RG, 98%);

[0058] 5-(11bR)-Dinaphtho[2,1-d:1',2'-f][1,3,2]dioxaphosphepin-4-yl)-5H-dibenzo[b,f]azepine (Biotrend);

[0059] Dichloromethane (Adamas, Water ≤ 50 ppm (by K.F.), 99.9%).

[0060] 1 H NMR, 13 C NMR, 19 F NMR spectra were obtained on a JEOL JNM-ECZ400S NMR spectrometer. Chemical shift values are in ppm, coupling constants in Hz, and high resolution mass spectra were obtained using a Thermo Fisher Scientific UPLC-ESI-Q-Orbitrap MS mass spectrometer.

[0061] As known from the foregoing, the prior art synthesis of vinyl dihydrofuran compounds is mainly intramolecular reaction, the source of raw materials is not easy, the preparation process is relatively complex, and the reaction system is difficult to replicate. How to synthesize vinyl dihydrofuran compounds by a simple step is an urgent problem to be solved.

[0062] Based on this, the first aspect of the embodiments of the present application provides a 4-vinyl dihydrofuran-3,3(2H)-disulfonyl difluoride compound having a structure as shown in formula 1:

[0063]

[0064] R is selected from one of methyl, methoxy, phenyl, fluorine atom, chlorine atom, bromine atom, nitro.

[0065] In some embodiments, the formula 1 comprises a structure as shown in the following formula 3 to formula 9:

[0066]

[0067]

[0068] The 4-vinyl dihydrofuran-3,3(2H)-disulfonyl difluoride compound provided by the embodiment can at least bring the following beneficial effects:

[0069] The embodiment of the present application uses a simple and readily available substituted 1,3-butadiene-1,1-disulfonyl difluoride compound as a raw material, and a cheap and readily available Pd2dba3·CHCl3 as a catalyst, to obtain a series of 4-vinyl dihydrofuran-3,3(2H)-disulfonyl difluoride compounds through a [3+2] cycloaddition reaction.

[0070] The second aspect of the embodiment of the present application provides a preparation method of a 4-vinyl dihydrofuran-3,3(2H)-disulfonyl difluoride compound, comprising the following steps:

[0071] The substituted 1,3-butadiene-1,1-disulfonyl difluoride compound, ethylene oxide, the catalyst and the ligand are mixed, and a [3+2] cycloaddition reaction is carried out in an organic solvent, and then 4-vinyl dihydrofuran-3,3(2H)-disulfonyl difluoride compounds are obtained after filtration, extraction and purification by silica gel column chromatography.

[0072] In some embodiments, the substituted 1,3-butadiene-1,1-disulfonyl difluoride compound has a structure as shown in formula 2:

[0073]

[0074] R is selected from one of methyl, methoxy, phenyl, fluorine atom, chlorine atom, bromine atom, nitro.

[0075] In some embodiments, the catalyst is tris(dibenzylideneacetone)dipalladium-chloroform adduct.

[0076] In some embodiments, the ligand is L2.

[0077] In some embodiments, the organic solvent is dichloromethane.

[0078] In some embodiments, when the organic solvent is dichloromethane, the ratio of the amount of dichloromethane to the substituted 1,3-butadiene-1,1-disulfonyl difluoride compound is 1.0 mL: 0.05-0.15 mmol.

[0079] Preferably, the ratio of the amount of dichloromethane to the substituted 1,3-butadiene-1,1-disulfonyl difluoride compound is 1.0 mL: 0.08-0.12 mmol.

[0080] More preferably, the ratio of the amount of dichloromethane to the substituted 1,3-butadiene-1,1-disulfonyl difluoride compound is 1.0 mL: 0.1 mmol.

[0081] In some embodiments, the molar ratio of the substituted 1,3-butadiene-1,1-disulfonyl difluoride compound, ethylene oxide, catalyst, and ligand is 1: (1-2): (0.01-0.04): (0.005-0.015).

[0082] Preferably, the molar ratio of the substituted 1,3-butadiene-1,1-disulfonyl difluoride compound, ethylene oxide, catalyst, and ligand is 1: (1.2-1.8): (0.02-0.03): (0.008-0.012).

[0083] More preferably, the molar ratio of the substituted 1,3-butadiene-1,1-disulfonyl difluoride compound, ethylene oxide, catalyst, and ligand is 1: 1.5: 0.025: 0.01, mainly because the vinyl ethylene oxide can dimerize itself, and side reactions can occur, requiring an excess of vinyl ethylene oxide.

[0084] In some embodiments, the specific conditions for the [3+2] cycloaddition reaction are:

[0085] The reaction temperature is 20-40°C, and the reaction time is 30-50 h.

[0086] Preferably, the specific conditions for the [3+2] cycloaddition reaction are:

[0087] The reaction temperature is 25-35°C, and the reaction time is 35-45 h.

[0088] More preferably, the specific conditions for the [3+2] cycloaddition reaction are:

[0089] The reaction temperature is 30°C, and the reaction time is 39 h.

[0090] In some embodiments, the filtering condition is that the substituted 1,3-butadiene-1,1-disulfonyl difluoride compound, ethylene oxide, catalyst and ligand completely disappear by TLC monitoring.

[0091] Specifically, the substituted 1,3-butadiene-1,1-disulfonyl difluoride compound is completely reacted, and the conversion rate is the highest, and better separation is performed.

[0092] More specifically, the filtering uses a sand core funnel paved with diatomite and silica gel on the upper layer.

[0093] In addition, during extraction, saturated brine is added, and the crude product is obtained by ethyl acetate extraction, wherein 5 milliliters of saturated brine and 5 milliliters of dichloromethane are used each time, and the extraction is performed three times. When the crude product is purified by silica gel column chromatography, a mixed solvent with a volume ratio of petroleum ether to ethyl acetate of 100:1 is used as the developing agent.

[0094] The preparation method of the 4-vinyl dihydrofuran-3,3(2H)-disulfonyl difluoride compound provided by the embodiments of the present application can at least bring the following beneficial effects:

[0095] 1. Compared with the prior art, the traditional method of the ethenyl dihydrofuran compound mainly uses intramolecular reaction. The present application combines the sulfonyl fluoride reagent with the five-membered heterocyclic skeleton, uses the substituted 1,3-butadiene-1,1-disulfonyl difluoride compound which is simple and easy to obtain as a raw material, and uses the cheap and easy-to-obtain Pd2dba3·CHCl3 as a catalyst. Through [3+2] cycloaddition reaction, a series of 4-vinyl dihydrofuran-3,3(2H)-disulfonyl difluoride compounds are obtained.

[0096] 2. The cycloaddition reaction induced by the ring tension has good reaction activity and excellent chemical and stereoselectivity. The ethylene oxide is used as a three-atom component, and the five-membered heterocyclic skeleton can be constructed in a regionally and stereoselective manner.

[0097] The third aspect of the embodiments of the present application provides a use of the 4-vinyl dihydrofuran-3,3(2H)-disulfonyl difluoride compound in an anticancer drug.

[0098] The above embodiments will be described in more detail below in combination with specific examples.

[0099] Preparation Example

[0100] Example 1

[0101] The present embodiment provides a preparation method of (E)-2-styryl-4-vinyl dihydrofuran-3,3(2H)-disulfonyl difluoride, which is shown in Figure 1 , which comprises the following steps:

[0102] In a 10 mL Schlenk tube, cinnamaldehyde (660.8 mg, 5 mmol) was added and flushed with nitrogen. Then dichloromethane (2 mL) and methylenedisulfonyl fluoride (946 mg, 5.25 mmol) were added. After dissolution, n-hexane (10 mL) was added on top of the dichloromethane phase and left at room temperature for 1-3 d. The crystalline product was collected by filtration and washed with dichloromethane / n-hexane mixture 1:5 (2 x 3 mL) and dried to collect the solid (E)-4-phenyl-1,3-butadiene-1,1-disulfonyl difluoride, i.e. the following structure:

[0103]

[0104] (1) A 10 mL Schlenk tube was dried under reduced pressure with a hot gun, flushed with nitrogen three times, and then left to return to room temperature. Pd2dba3-CHCl3(7.8 mg, 0.0075 mmol), L2(15.0 mg, 0.03 mmol) were added and flushed with nitrogen three times, 3 mL of anhydrous dichloromethane was added, and stirred at room temperature for 30 min. (E)-4-phenyl-1,3-butadiene-1,1-disulfonyl difluoride (88.3 mg, 0.3 mmol), vinyl oxirane (31.5 mg, 0.45 mmol) were added, and reacted at 30 °C for 39 h.

[0105] (2) The reaction was monitored by TLC until the starting material was consumed to obtain a product mixture solution, which was filtered to remove the precipitate using a sand core funnel with diatomite and silica gel on top; saturated brine (5 mL) was added, and extracted with ethyl acetate (5 mL) three times.

[0106] (3) The crude product was purified by silica gel column chromatography, using a mixed solvent of petroleum ether and ethyl acetate in a volume ratio of 100:1 as the developing agent, to obtain a white solid (95 mg, yield 87%), i.e. (E)-2-styryl-4-vinyl dihydrofuran-3,3(2H)-disulfonyl difluoride, with the following structure:

[0107]

[0108] The basic parameters are as follows:

[0109] See Figure 2 , Figure 3 and Figure 4 , the basic parameters of the compound are as follows:

[0110] 1H NMR (400 MHz, CDC13): δ 7.47 - 7.41 (m, 2H), 7.39 - 7.29 (m, 3H), 6.96 (d, J = 15.9 Hz, 1H), 6.37 (dd, J = 15.9, 7.1 Hz, 1H), 6.07 - 5.96 (m, 1H), 5.58 (d, J = 1.8 Hz, 1H), 5.54 (d, J = 5.2 Hz, 1H), 5.38 - 5.30 (m, 1H), 4.43 - 4.36 (m, 1H), 4.05 - 3.85 (m, 2H).

[0111] 19 F NMR (376 MHz, CDC13): δ 63.27, 62.19 (d, J = 9.7 Hz).

[0112] 13 C NMR (101 MHz, CDC13): δ 138.5, 135.2, 129.3, 128.9, 127.4, 126.4, 125.6, 118.6, 94.9 (t, J = 11.8 Hz), 86.5, 71.5, 53.2.

[0113] HRMS (ESI): m / z Calcd for C 14 H 14 F2O5S2Na [M + Na] + : 387.0143, found 387.0144.

[0114] Example 2

[0115] This example provides a method for preparing (E)-2-(2-methoxy styryl)-4- vinyl dihydrofuran-3,3(2H)-disulfonyl difluoride, see Figure 1 , comprising the steps of:

[0116] Into a 10 mL Schlenk tube was added (E)-3-(2-methoxyphenyl)acrylaldehyde (810.4 mg, 5 mmol) and flushed with nitrogen. Then dichloromethane (2 mL) and methylene disulfonyl fluoride (946 mg, 5.25 mmol) were added. After dissolution, n-hexane (10 mL) was added on top of the dichloromethane phase and left at room temperature for 1-3 d. The crystalline product was collected by filtration and washed with dichloromethane / n-hexane mixture 1:5 (2 x 3 mL) and dried to collect the solid (E)-4-(2-methoxyphenyl)-1,3-butadiene-1,1- disulfonyl difluoride, i.e., the following structural formula:

[0117]

[0118] (1) Under nitrogen protection, 10 mL Shrek tubes were dried under reduced pressure using a hot air gun and purged with nitrogen three times. After returning to room temperature, Pd2dba3·CHCl3 (7.8 mg, 0.0075 mmol) and L2 (15.0 mg, 0.03 mmol) were added, and nitrogen was purged three times. Then, 3 mL of anhydrous dichloromethane was added, and the mixture was stirred at room temperature for 30 min. (E)-4-(2-methoxyphenyl)-1,3-butadiene-1,1-disulfonyl difluoride (97.3 mg, 0.3 mmol) and vinyl ethylene oxide (31.5 mg, 0.45 mmol) were added, and the mixture was reacted at 30 °C for 39 h.

[0119] (2) Monitor the reaction raw materials with TLC until they disappear, and obtain a mixed solution of products. Filter the solution with a sand core funnel with diatomaceous earth and silica gel on the top to remove the precipitate. Add saturated saline (5 ml) and extract three times with ethyl acetate (5 ml).

[0120] (3) The crude product was purified by silica gel column chromatography using a mixed solvent of petroleum ether and ethyl acetate in a volume ratio of 100:1. This yielded a white solid (104.8 mg, yield 89%), namely (E)-2-(2-methoxystyryl)-4-vinyldihydrofuran-3,3(2H)-disulfonyldifluoride, with the following structural formula:

[0121]

[0122] See Figure 5 , Figure 6 and Figure 7 The basic parameters of this compound are as follows:

[0123] 1 H NMR (400MHz, CDCl) 3； mixture of diastereomers): δ7.45(dd,J=7.7,1.7Hz,1H),7.33–7.18(m,3H),6.96(td,J=7.5,1.1Hz,1H),6 .89(dd,J=8.3,1.1Hz,1H),6.47–6.38(m,1H),6.06–5.97(m,1H),5.58(dd,J=1.9,0.9Hz,0.97H), 5.54(dd,J=4.6,0.9Hz,0.82H),5.50(dd,J=3.6,1.3Hz,0.12H),5.46(dd,J=3.5,1Hz,0.11H),5. 34(t,J=8.3Hz,1H),4.42–4.36(m,1H),4.02–4.09(m,0.24H),4.01–3.87(m,1.98H),3.86(s,3H).

[0124] 19 F NMR (376MHz, CDCl) 3； mixture of diastereomers): δ72.79, 63.32, 62.22 (d, J = 7.1Hz), 57.42 (d, J = 8.8Hz). 13 C NMR (101MHz, CDCl) 3； mixture of diastereomers): δ157.5,134.0,130.4,128.1,126.6,125.5,124.27,120.9, 119.7,119.1,111.1,95.1(t,J=10.6Hz),87.3,86.7,71.4,55.6,53.3,52.1.

[0125] HRMS(ESI): m / z Calcd for C 15 H 16 F₂O₆S₂Na[M+Na] + :417.0248,found417.0248.

[0126] Example 3

[0127] This embodiment provides a method for preparing (E)-2-(2-chlorostyryl)-4-vinyldihydrofuran-3,3(2H)-disulfonyldifluoride, see [link to relevant documentation]. Figure 1 This includes the following steps:

[0128] Add (E)-3-(2-chlorophenyl)propenal (833.0 mg, 5 mmol) to a 10 mL Schlenk tube and rinse with nitrogen. Then add dichloromethane (2 mL) and methylene disulfonyl fluoride (946 mg, 5.25 mmol). After dissolution, add n-hexane (10 mL) on top of the dichloromethane phase and let stand at room temperature for 1–3 days. Filter to collect the crystallized product, wash with a 1:5 (2 × 3 mL) dichloromethane / n-hexane mixture, dry, and collect the solid (E)-4-(2-chlorophenyl)-1,3-butadiene-1,1-disulfonyl difluoride, with the following structural formula:

[0129]

[0130] (1) Under nitrogen protection, 10 mL Schlenk tube was dried by hot gun under reduced pressure, replaced with nitrogen for three times. After returning to room temperature, Pd2dba3CHCl3(7.8 mg, 0.0075 mmol), L2(15.0 mg, 0.03 mmol) were added and replaced with nitrogen for three times, 3 mL anhydrous dichloromethane was added, stirred at room temperature for 30 min. (E)-4-(2-chlorophenyl)-1,3-butadiene-1,1-disulfonyl difluoride (98.6 mg, 0.3 mmol), vinyl oxirane (31.5 mg, 0.45 mmol) were added, and reacted at 30°C for 39 h.

[0131] (2) The reaction was monitored by TLC until the starting material was consumed, and the product mixture solution was obtained. The precipitate was removed by filtering with the sand core funnel filled with diatomite and silica gel. Saturated brine (5 mL) was added, and extracted with ethyl acetate (5 mL) for three times.

[0132] (3) The crude product was purified by silica gel column chromatography, and the developing agent was a mixed solvent of petroleum ether and ethyl acetate with a volume ratio of 100:1, to obtain white solid (95.5 mg, yield 80%), namely (E)-2-(2-chlorostyryl)-4-vinyl dihydrofuran-3,3(2H)-disulfonyl difluoride, with the structural formula as follows:

[0133]

[0134] See Figure 8 , Figure 9 and Figure 10 , the basic parameters of the compound are as follows:

[0135] 1 H NMR (400 MHz, CDC13; mixture of diastereomers): δ 7.60-7.51 (m, 1H), 7.41-7.32 (m, 2H), 7.31-7.26 (m, 2H), 6.34 (dtd, J = 15.5, 7.1, 1.8 Hz, 1H), 6.08-5.97 (m, 1H), 5.59 (d, J = 1.6 Hz, 0.9H), 5.57-5.54 (m, 0.78H), 5.51 (d, J = 1.6 Hz, 0.2H), 5.49-5.48 (m, 0.17H), 5.45-5.41 (ddd, J = 8.2, 7.4, 1.6 Hz, 0.19H), 5.38 (ddd, J = 8.5, 6.8, 1.3 Hz, 0.81H), 4.47-4.36 (m, 1H), 4.23-4.13 (m, 0.36H), 4.05-3.89 (m, 1.71H).

[0136] 19F NMR (376 MHz, CDC13; mixture of diastereomers): δ 72.87, 63.42, 62.05 (d, J = 9.9 Hz), 57.61 (d, J = 8.8 Hz).

[0137] 13 C NMR (101 MHz, CDC13; mixture of diastereomers): δ 134.8, 133.9, 133.7, 133.5, 130.2, 130.1, 129.9, 127.8, 127.3, 126.4, 126.2, 125.8, 121.5, 94.9 (t, J = 14.7 Hz), 86.2, 85.5, 71.6, 53.3.

[0138] HRMS (ESI): m / z Calcd for C 14 H 13 ClF2O5S2Na [M + Na] + : 420.9753, found 420.9753.

[0139] Example 4

[0140] This example provides a method for preparing (E)-2-(2-bromostyryl)-4- vinyldihydrofuran-3,3(2H)-disulfonic difluoride, see Figure 1 , comprising the steps of:

[0141] Into a 10 mL Schlenk tube was added (E)-3-(2-bromophenyl)acrylaldehyde (1.86 g, 5 mmol) and flushed with nitrogen. Then dichloromethane (2 mL) and methylene disulfonic difluoride (946 mg, 5.25 mmol) were added. After dissolution, n-hexane (10 mL) was added on top of the dichloromethane phase and left at room temperature for 1-3 d. The crystalline product was collected by filtration and washed with a dichloromethane / n-hexane mixture 1:5 (2 x 3 mL) and dried to collect the solid (E)-4-(2-bromophenyl)-1,3- butadiene-1,1-disulfonic difluoride, i.e. the following structural formula:

[0142]

[0143] (1) Under nitrogen protection, 10 mL Schlenk tube was dried by hot gun under reduced pressure, replaced with nitrogen three times. After returning to room temperature, Pd2dba3CHCl3(7.8 mg, 0.0075 mmol), L2(15.0 mg, 0.03 mmol) were added and replaced with nitrogen three times, 3 mL anhydrous dichloromethane was added, and stirred at room temperature for 30 min. (E)-4-(2-bromophenyl)-1,3-butadiene-1,1-disulfonic difluoride (111.9 mg, 0.3 mmol), vinyl oxirane (31.5 mg, 0.45 mmol) were added, and reacted at 30°C for 39 h.

[0144] (2) TLC was used to monitor the disappearance of the reaction raw materials to obtain a product mixed solution, which was filtered to remove the precipitate with a sand core funnel filled with diatomite and silica gel; saturated brine (5 mL) was added, and extracted with ethyl acetate (5 mL) three times.

[0145] (3) The crude product was purified by silica gel column chromatography, and the developing agent was a mixed solvent of petroleum ether and ethyl acetate in a volume ratio of 100:1, to obtain a white solid (78.2 mg, yield 59%), namely (E)-2-(2-bromostyryl)-4-vinyl dihydrofuran-3,3(2H)-disulfonic difluoride, with the structural formula as follows:

[0146]

[0147] See Figure 11 , Figure 12 and Figure 13 The basic parameters of the compound are as follows:

[0148] 1 H NMR (400 MHz, CDC13; mixture of diastereomers): δ 7.56 (ddt, J = 13.1, 7.7, 1.5 Hz, 2H), 7.37-7.25 (m, 2H), 7.25-7.15 (m, 1H), 6.29 (dddd, J = 15.7, 7.7, 6.7, 1.8 Hz, 1H), 6.07-5.95 (m, 1H), 5.61-5.54 (m, 1H), 5.50 (dd, J = 13.5, 3.4 Hz, 1H), 5.46-5.34 (m, 1H), 4.48-4.33 (m, 1H), 4.24-4.13 (m, 1H), 4.06-3.90 (m, 1H).

[0149] 19F NMR (376 MHz, CDC13; mixture of diastereomers): δ 72.88, 63.47, 62.02 (d, J = 8.8 Hz), 57.66 (d, J = 9.5 Hz).

[0150] 13 C NMR (101 MHz, CDC13; mixture of diastereomers): δ 137.3, 136.1, 135.6, 135.5, 133.1, 130.4, 130.3, 128.4, 128.0, 127.9, 127.9, 126.4, 125.8, 124.3, 124.1, 122.3, 121.6, 94.9 (t, J = 10.1 Hz), 93.9 (t, J = 9.1 Hz), 86.0, 85.2, 71.6, 71.36, 53.2, 52.2.

[0151] HRMS (ESI): m / z Calcd for C 14 H 13 BrF2O5S2Na [M+Na] + : 464.9248, found 464.9252.

[0152] Example 5

[0153] This example provides a method for preparing (E)-2-(3-methylstyryl)-4- vinyldihydrofuran-3,3(2H)-disulfonic difluoride, see Figure 1 , comprising the steps of:

[0154] Into a 10 mL Schlenk tube was added (E)-3-m-methylcinnamaldehyde (730.9 mg, 5 mmol) and flushed with nitrogen. Then dichloromethane (2 mL) and methylene disulfonic difluoride (946 mg, 5.25 mmol) were added. After dissolution, n-hexane (10 mL) was added on top of the dichloromethane phase and left at room temperature for 1-3 d. The crystalline product was collected by filtration and washed with dichloromethane / n-hexane 1:5 (2 x 3 mL) and dried to collect the solid (E)-4-(3-methylphenyl)-1,3-butadiene-1,1- disulfonic difluoride, i.e. the following structural formula:

[0155]

[0156] (1) Under nitrogen protection, 10 mL Schlenk tube was dried by hot gun under reduced pressure, replaced with nitrogen for three times. After returning to room temperature, Pd2dba3CHCl3(7.8 mg, 0.0075 mmol), L2(15.0 mg, 0.03 mmol) were added and replaced with nitrogen for three times, 3 mL anhydrous dichloromethane was added, stirred at room temperature for 30 min. (E)-4-(3-methylphenyl)-1,3-butadiene-1,1-disulfonyl difluoride (92.4 mg, 0.3 mmol), vinyl oxirane (31.5 mg, 0.45 mmol) were added, and reacted at 30°C for 39 h.

[0157] (2) TLC was used to monitor the disappearance of the reaction raw materials to obtain a product mixed solution; the precipitate was removed by filtering through a sand core funnel filled with diatomite and silica gel; saturated brine (5 mL) was added and extracted with ethyl acetate (5 mL) three times.

[0158] (3) The crude product was purified by silica gel column chromatography, and the developing agent was a mixed solvent of petroleum ether and ethyl acetate in a volume ratio of 100:1, to obtain a yellow liquid (55.5 mg, yield 49%) of (E)-2-(3-methylstyryl)-4-vinyl dihydrofuran-3,3(2H)-disulfonyl difluoride, with the structural formula as follows:

[0159]

[0160] The basic parameters of the compound are as follows:

[0161] 1 H NMR (400 MHz, CDCl3): δ 7.30-7.21 (m, 3H), 7.16 (ddt, J = 5.9, 4.2, 2.6 Hz, 1H), 6.93 (dt, J = 16.0, 1.3 Hz, 1H), 6.36 (ddd, J = 15.9, 7.1, 1.2 Hz, 1H), 6.02 (dddd, J = 18.0, 9.5, 8.0, 1.4 Hz, 1H), 5.59 (dd, J = 1.7, 0.8 Hz, 1H), 5.55 (dd, J = 4.9, 0.9 Hz, 1H), 5.33 (ddd, J = 8.7, 7.1, 1.2 Hz, 1H), 4.45-4.37 (m, 1H), 4.04-3.87 (m, 2H), 2.37 (s, 3H).

[0162] 19 F NMR (376 MHz, CDCl3): δ 63.24, 62.19 (d, J = 8.5 Hz).

[0163] 13C NMR (101 MHz, CDC13): δ 138.7, 138.6, 135.1, 130.1, 128.8, 128.0, 126.5, 125.6, 124.6, 118.3, 94.9 (t, J = 11.6 Hz), 86.6, 71.5, 53.3, 21.5.

[0164] HRMS (ESI): m / z Calcd for C 15 H 16 F2O5S2Na[M+Na] + :401.0299, found401.0299.

[0165] Example 6

[0166] This example provides a method for preparing (E)-2-(4-fluorostyryl)-4- vinyldihydrofuran-3,3(2H)-disulfonic difluoride, see Figure 1 , comprising the following steps:

[0167] Into a 10 mL Schlenk tube was added (E)-3-(4-fluorophenyl)acrylaldehyde (750.7 mg, 5 mmol) and flushed with nitrogen. Then dichloromethane (2 mL) and methylenedisulfonic difluoride (946 mg, 5.25 mmol) were added. After dissolution, n-hexane (10 mL) was added on top of the dichloromethane phase and left at room temperature for 1-3 d. The crystalline product was collected by filtration and washed with dichloromethane / n-hexane 1:5 (2 x 3 mL) and dried to collect the solid (E)-4-(4-fluorophenyl)-1,3-butadiene-1,1- disulfonic difluoride, i.e. the following structural formula:

[0168]

[0169] (1) A 10 mL Schlenk tube was dried under reduced pressure with a hot gun, flushed with nitrogen three times, and then allowed to return to room temperature. Pd2dba3-CHCl3(7.8 mg, 0.0075 mmol), L2(15.0 mg, 0.03 mmol) were added and flushed with nitrogen three times, 3 mL of anhydrous dichloromethane was added, and stirred at room temperature for 30 min. (E)-4-(4-fluorophenyl)-1,3-butadiene-1,1-disulfonic difluoride (93.6 mg, 0.3 mmol), vinyl oxirane (31.5 mg, 0.45 mmol) were added, and reacted at 30 °C for 39 h.

[0170] (2) The reaction was monitored by TLC until the starting material was consumed to obtain a product mixed solution; the precipitate was removed by filtration using a sand core funnel with diatomite and silica gel on top; saturated brine (5 mL) was added, and extracted with ethyl acetate (5 mL) three times.

[0171] (3) The crude product was purified by silica gel column chromatography, and the developing agent was a mixture of petroleum ether and ethyl acetate with a volume ratio of 100:1, to obtain a yellow liquid (96.4 mg, yield 84%), namely (E)-2-(4-fluorostyryl)-4-vinyldihydrofuran-3,3(2H)-disulfonic difluoride, with a structural formula as follows:

[0172]

[0173] The basic parameters of the compound are as follows:

[0174] 1 H NMR (400 MHz, CDC13): δ 7.48-7.38 (m, 2H), 7.11-7.00 (m, 2H), 6.92 (d, J = 15.9 Hz, 1H), 6.29 (ddd, J = 15.9, 7.0, 1.2 Hz, 1H), 6.01 (dddd, J = 18.5, 9.6, 8.0, 1.4 Hz, 1H), 5.59 (m, J = 1.0 Hz, 1H), 5.55 (dd, J = 5.5, 0.9 Hz, 1H), 5.32 (ddd, J = 8.5, 7.0, 1.2 Hz, 1H), 4.44-4.37 (m, 1H), 4.04-3.88 (m, 2H).

[0175] 19 F NMR (376 MHz, CDC13): δ 63.20, 62.21 (d, J = 9.2 Hz), -111.70.

[0176] 13 C NMR (101 MHz, CDC13): δ 164.6, 162.1, 137.2, 131.4 (d, J = 4.4 Hz, 1H), 129.1 (d, J = 8.5 Hz, 1H), 126.4, 125.7, 118.4, 116.1, 115.9, 94.9 (t, J = 11.1 Hz), 86.4, 71.5, 53.3.

[0177] HRMS (ESI): m / z Calcd for C 14 H 14 F3O5S2[M+H] + : 383.0229, found 383.0227.

[0178] Example 7

[0179] The present embodiment provides a method for preparing (E)-2-(4-nitrostyryl)-4-vinyldihydrofuran-3,3(2H)-disulfonyl difluoride, see Figure 1 , comprising the following steps:

[0180] In a 10 mL Schlenk tube, (E)-3-(4-bromophenyl)acrylaldehyde (1.1 g, 5 mmol) was added and flushed with nitrogen. Then dichloromethane (2 mL) and methylene disulfonyl fluoride (946 mg, 5.25 mmol) were added. After dissolution, n-hexane (10 mL) was added on top of the dichloromethane phase, and left at room temperature for 1-3 d. The crystalline product was collected by filtration, washed with dichloromethane / n-hexane mixture 1:5 (2 x 3 mL), dried, and the solid (E)-4-(4-nitrophenyl)-1,3-butadiene-1,1-disulfonyl difluoride was collected, which has the following structure:

[0181]

[0182] (1) Under nitrogen protection, a 10 mL Schlenk tube was dried with a hot oven gun under reduced pressure, and nitrogen was replaced three times. After returning to room temperature, Pd2dba3·CHCl3(7.8 mg, 0.0075 mmol), L2(15.0 mg, 0.03 mmol) were added and replaced with nitrogen three times, 3 mL of anhydrous dichloromethane was added, and stirred at room temperature for 30 min. (E)-4-(4-nitrophenyl)-1,3-butadiene-1,1-disulfonyl difluoride (101.7 mg, 0.3 mmol), vinyl oxirane (31.5 mg, 0.45 mmol) were added, and reacted at 30°C for 39 h.

[0183] (2) The reaction was monitored by TLC until the raw materials were consumed, and a product mixture solution was obtained; the precipitate was removed by filtering through a sand core funnel filled with diatomite and silica gel; saturated brine (5 mL) was added, and extracted with ethyl acetate (5 mL) three times.

[0184] (3) The crude product was purified by silica gel column chromatography, and the developing agent was a mixed solvent of petroleum ether and ethyl acetate in a volume ratio of 100:1, and a white solid (57.4 mg, yield 47%) was obtained, which was (E)-2-(4-nitrostyryl)-4-vinyldihydrofuran-3,3(2H)-disulfonyl difluoride, and had the following structure:

[0185]

[0186] The basic parameters of the compound are as follows:

[0187] 1H NMR (400 MHz, CDC13): δ 8.26 - 8.20 (m, 2H), 7.61 - 7.55 (m, 2H), 7.03 (d, J = 16.0 Hz, 1H), 6.52 (dd, J = 16.0, 6.2 Hz, 1H), 6.01 (dddd, J = 19.1, 9.5, 7.9, 1.5 Hz, 1H), 5.61 (m, 1H), 5.57 (d, J = 6.5 Hz, 1H), 5.36 (ddd, J = 8.8, 6.3, 1.4 Hz, 1H), 4.44 (ddd, J = 7.8, 6.2, 1.7 Hz, 1H), 4.06 - 3.88 (m, 2H).

[0188] 19 F NMR (376 MHz, CDC13): δ 63.35, 62.03 (d, J = 8.2 Hz).

[0189] 13 C NMR (101 MHz, CDC13): δ 148.0, 141.4, 135.5, 128.0, 126.1, 125.9, 124.3, 123.2, 94.8 (t, J = 14.8 Hz), 85.4, 71.7, 53.2.

[0190] HRMS (ESI): m / z Calcd for C 14 H 13 F2NO7S2Na [M + Na] + : 431.9993, found 431.9996.

[0191] Example 8

[0192] This example provides a method for preparing (E)-2-(2-([1,1'-biphenyl]-4- yl)ethenyl)-4-vinyldihydrofuran-3,3(2H)-disulfonic difluoride, see Figure 1 , comprising the steps of:

[0193] Into a 10 mL Schlenk tube was added (E)-3-([1,1'-biphenyl]-4-yl)prop-2- enal (1.0 g, 5 mmol) and flushed with nitrogen. Then dichloromethane (2 mL) and methylenedisulfonic difluoride (946 mg, 5.25 mmol) were added. After dissolution, n-hexane (10 mL) was added on top of the dichloromethane phase and left at room temperature for 1-3 d. The crystalline product was collected by filtration and washed with dichloromethane / n-hexane 1:5 (2 x 3 mL) and dried to collect the solid (E)-4-([1,1'-biphenyl]-4-yl)-1,3-butadiene-1,1- disulfonic difluoride, i.e. the following structural formula:

[0194]

[0195] (1) Under nitrogen protection, 10 mL Schlenk tube was dried by hot gun under reduced pressure, replaced with nitrogen three times. After returning to room temperature, Pd2dba3·CHCl3(7.8 mg, 0.0075 mmol), L2(15.0 mg, 0.03 mmol) were added and replaced with nitrogen three times, 3 mL anhydrous dichloromethane was added, and stirred at room temperature for 30 min. (E)-4-([1,1'-biphenyl]-4-yl)-1,3-butadiene-1,1-disulfonic difluoride (111.0 mg, 0.3 mmol), vinyl oxirane (31.5 mg, 0.45 mmol) were added, and reacted at 30°C for 39 h.

[0196] (2) TLC was used to monitor the disappearance of the reaction raw materials to obtain a product mixed solution; the precipitate was removed by filtering with a sand core funnel filled with diatomite and silica gel; saturated brine (5 mL) was added, and extracted with ethyl acetate (5 mL) three times.

[0197] (3) The crude product was purified by silica gel column chromatography, and the developing agent was a mixed solvent of petroleum ether and ethyl acetate in a volume ratio of 100:1. White solid (67.5 mg, yield 51%) was obtained, which was (E)-2-(2-([1,1'-biphenyl]-4-yl)enyl)-4-vinyl dihydrofuran-3,3(2H)-disulfonic difluoride, and the structural formula was as follows:

[0198]

[0199] The basic parameters of the compound are as follows:

[0200] 1 H NMR (400 MHz, CDCl3): δ 7.63-7.56 (m, 4H), 7.55-7.50 (m, 2H), 7.48-7.42 (m, 2H), 7.39-7.34 (m, 1H), 7.00 (d, J = 15.9 Hz, 1H), 6.41 (ddd, J = 15.9, 7.1, 1.1 Hz, 1H), 6.08-5.96 (m, 1H), 5.62-5.55 (m, 2H), 5.40-5.33 (m, 1H), 4.46-4.41 (m, 1H), 4.08-3.90 (m, 2H).

[0201] 19 F NMR (376 MHz, CDCl3): δ 63.25, 62.23 (d, J = 6.8 Hz).

[0202] 13C NMR (101 MHz, CDC13): δ 142.1, 140.5, 138.0, 134.1, 129.0, 127.9, 127.8, 127.6, 127.2, 126.5, 125.7, 118.5, 94.9 (t, J = 13.2 Hz), 86.5, 71.5, 53.3.

[0203] HRMS (ESI): m / z Calcd for C 20 H 19 F2O5S2[M+H] + : 441.0637, found 441.0634.

[0204] Comparative Example 1

[0205] Mostly the same as Example 1 except Pd2dba3-CHCl3 was replaced by PdCl2, no product was observed.

[0206] Comparative Example 2

[0207] Mostly the same as Example 1 except Pd2dba3-CHCl3 was replaced by PdCl2(C6H5CN)2, no product was observed.

[0208] Comparative Example 3

[0209] Mostly the same as Example 1 except ligand L2 was replaced by diphenyl-2-pyridyl phosphine, the corresponding yield was only 32%.

[0210] Comparative Example 3

[0211] Mostly the same as Example 1 except ligand L2 was replaced by xantphos, the corresponding yield was only 11%.

[0212] Comparative Example 3

[0213] Mostly the same as Example 1 except ligand L2 was replaced by PPh3, the corresponding yield was only 5%.

[0214] The above description of the comparative examples is to enable a person of ordinary skill in the art to understand and use the invention. It will be apparent to those skilled in the art that various modifications can be made to the embodiments described herein without departing from the spirit and scope of the invention. Therefore, the invention is not limited to the above embodiments, and improvements and modifications made by those skilled in the art based on the disclosure of the invention without departing from the scope of the invention should be within the scope of the invention.

Claims

1. A method for preparing a 4-vinyldihydrofuran-3,3(2H)-disulfonyl difluoride compound, characterized in that, Includes the following steps: A mixture of substituted 1,3-butadiene-1,1-disulfonyl difluoride compounds, ethylene oxide, catalyst and ligands were subjected to a [3+2] cycloaddition reaction in an organic solvent. After filtration, extraction and purification by silica gel column chromatography, 4-vinyldihydrofuran-3,3(2H)-disulfonyl difluoride compounds were obtained. The catalyst is a tris(dibenzylacetone)dipalladium-chloroform adduct; The ligand is L2, and has the structure shown in Formula 11: Formula 11 The 4-vinyldihydrofuran-3,3(2H)-disulfonyl difluoride compounds have the structure shown in Formula 1: Formula 1 In the formula, R is selected from one of methyl, methoxy, phenyl, fluorine atom, chlorine atom, bromine atom, and nitro group.

2. The method for preparing a 4-vinyldihydrofuran-3,3(2H)-disulfonyl difluoride compound according to claim 1, characterized in that, The substituted 1,3-butadiene-1,1-disulfonyl difluoride compound has the structure shown in Formula 2: Formula 2 In the formula, R is selected from one of methyl, methoxy, phenyl, fluorine atom, chlorine atom, bromine atom, and nitro group.

3. The method for preparing a 4-vinyldihydrofuran-3,3(2H)-disulfonyl difluoride compound according to claim 1, characterized in that, The organic solvent is dichloromethane.

4. The method for preparing a 4-vinyldihydrofuran-3,3(2H)-disulfonyl difluoride compound according to claim 1, characterized in that, The molar ratio of the substituted 1,3-butadiene-1,1-disulfonyl difluoride compound, ethylene oxide, catalyst, and ligand is 1:(1~2):(0.01~0.04):(0.005~0.015).

5. The method for preparing a 4-vinyldihydrofuran-3,3(2H)-disulfonyl difluoride compound according to claim 1, characterized in that, The specific conditions for the [3+2] cycloaddition reaction are as follows: The reaction temperature is 20~40℃, and the reaction time is 30~50h.

6. The method for preparing a 4-vinyldihydrofuran-3,3(2H)-disulfonyl difluoride compound according to claim 1, characterized in that, The filtration conditions were: complete disappearance of substituted 1,3-butadiene-1,1-disulfonyl difluoride compounds, ethylene oxide, catalyst, and ligands as monitored by TLC.

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