A polyfluoroaryl-substituted sulfone compound, a synthesis method and application thereof

Abstract

The application discloses a polyfluoro aryl substituted sulfone compound and a synthesis method and application thereof, and the polyfluoro aryl substituted sulfone compound has a chemical structural formula. The synthesis method provided by the application directly uses a polyfluoro aromatic compound, DABSO and alkyl potassium trifluoroborate as synthesis raw materials under a photocatalysis condition, and a higher yield can be obtained at normal temperature, the method is environment-friendly, atomic utilization is high, conforms to a green chemical concept, and has excellent catalytic synthesis value and industrial application potential.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of sulfone compounds, in particular to a polyfluoroaryl-substituted sulfone compound and a synthesis method and application thereof. BACKGROUND

[0002] Polyfluoroaryl sulfone compounds have unique biological and pharmacological activities, and are widely present in bioactive molecules and drug molecules. As The following formula described A in For example, polyfluoroaryl sulfone derivative cyclopropyloxacin A has good antibacterial activity (Heterocyclic Chem., 2015, 53, 89); polyfluoroaryl sulfonamide B can be used as a carbonic anhydrase inhibitor (Bioorg. Med. Chem., 2013, 21, 2093); perfluoroaryl sulfonamide C can be used as an antitumor drug (Proc. Natl. Acad. Sci. USA, 1999, 96, 5686). At the same time, polyfluoroaryl sulfone compounds also have important applications in the field of material chemistry such as molecular adsorption and polymer photocatalysts. Therefore, it is of great value to develop new synthesis methods for polyfluoroaryl sulfone compounds.

[0003] A bioactive molecule and a drug molecule containing a polyfluoroaryl sulfone skeleton

[0004]

[0005] B Traditional method for synthesizing polyfluoroaryl sulfone compounds

[0006]

[0007] The above is the importance and synthesis method of polyfluoroaryl sulfone compounds

[0008] The traditional synthesis method for synthesizing polyfluoroaryl sulfone compounds is based on a two-step synthesis method the B above 1. Oxidation of polyfluoroaryl mercaptan using liquid bromine and fuming nitric acid to synthesize polyfluoroaryl sulfonyl bromide, and then obtaining a polyfluoroaryl sulfone skeleton through tandem functionalization (Russ. J. Org. Chem., 2011, 47, 374; Procedia Chem., 2015, 15, 265). 2. The synthesis of polyfluoroaryl sulfone can also be achieved through the nucleophilic substitution of thiol / thiophenol and polyfluoroarene and the tandem oxidation process. The above strategy provides a method for synthesizing important polyfluoroaryl sulfone compounds, but there are still problems such as complicated operation and poor functional group compatibility to be solved. SUMMARY

[0009] The application provides a three-component synthesis method of a polyfluoroaryl-substituted sulfone compound under mild conditions, wherein a polyfluoroarene compound, DABSO and alkyl potassium trifluoroborate are directly used as synthesis raw materials under photocatalytic conditions, the reaction condition is mild, energy saving and environment-friendly, no additional reducing agent or alkali needs to be added, the system is relatively simple, and the method has excellent catalytic synthesis value and industrial application potential.

[0010] The application is achieved by the following technical scheme:

[0011] In a first aspect, the application provides a polyfluoroaryl-substituted sulfone compound, and the chemical structural formula is as follows:

[0012]

[0013] Among them:

[0014] OR1 includes one of methoxy, isopropoxy, t-butoxy, phenoxy, benzyloxy and alkoxy derived from menthol, fructose diketone and ginger ketone;

[0015] R2 includes one of cyano, trifluoromethyl and ketone carbonyl;

[0016] R3 includes one of t-butyl, isopropyl, ethyl, n-butyl, cyclobutyl, cyclopentyl, cyclohexyl, substituted or unsubstituted benzyl.

[0017] The polyfluoroaryl-substituted sulfone compound provided by the application is a white solid, can be separated from a reaction system by a column chromatography method, and can be comprehensively characterized by nuclear magnetic resonance hydrogen spectrum, nuclear magnetic resonance carbon spectrum, nuclear magnetic resonance fluorine spectrum and high-resolution mass spectrometry.

[0018] In a second aspect, the application provides a synthesis method of a polyfluoroaryl-substituted sulfone compound, which is used for preparing the polyfluoroaryl-substituted sulfone compound, and comprises the following steps:

[0019] In an inert atmosphere, under the action of a photocatalyst, the reactant is subjected to a photocatalytic reaction under visible light irradiation in a solvent to prepare the polyfluoroaryl-substituted sulfone compound.

[0020] The reactant comprises a polyfluoroarene compound, a bis(dioxidosulfur)-1,4-diazabicyclo[2.2.2]octane adduct (DABSO) and alkyl potassium trifluoroborate.

[0021] The present application realizes synthesis of polyfluoroaryl-substituted sulfone compounds under photocatalytic conditions, using polyfluoroarene compounds, DABSO and alkyl potassium trifluoroborate as raw materials. Compared with traditional heating reactions, visible light catalytic reactions have the advantages of simple experimental operation, mild conditions, high functional group tolerance, wide application range, energy saving and environmental protection, etc. The present application does not need to add additional reducing agents, organic bases or inorganic bases, and the reaction can occur at room temperature, with high yield and high atom utilization rate, in line with the synthesis concept of green chemistry. The present application is successfully applied to the synthesis of various polyfluoroaryl-substituted sulfone compounds, and has excellent catalytic synthesis value and industrial application potential.

[0022] In a third aspect, the present application provides the use of the above-mentioned polyfluoroaryl-substituted sulfone compounds or the polyfluoroaryl-substituted sulfone compounds synthesized by the above-mentioned synthesis method in the field of medicine.

[0023] The present application provides the above-mentioned polyfluoroaryl-substituted sulfone compounds, which can be applied to the late-stage modification of active pharmaceutical molecules.

[0024] The present application can synthesize the following polyfluoroaryl-substituted sulfone compounds:

[0025]

[0026] 4ea is a corresponding ester containing menthol structure. Menthol can be used as a flavoring agent for toothpaste, perfume, beverage and candy, etc. In medicine, it is used as a stimulant, acting on the skin or mucous membrane, and has a cooling and itching-relieving effect. It can be used as a wind-drivin agent for internal use, and is used for inflammation of the nose, throat and throat, etc. The present application can modify natural products or active pharmaceutical molecules such as menthol to synthesize polyfluoroaryl-substituted sulfone compounds such as 4ea.

[0027] The present application has the following advantages and beneficial effects:

[0028] The present application uses polyfluoroarene compounds, DABSO and alkyl potassium trifluoroborate as raw materials under room temperature conditions, without adding additional reducing agents or bases, to prepare polyfluoroaryl-substituted sulfone compounds by reaction. The present application has the following advantages:

[0029] 1. The present application uses polyfluoroaryl sulfone, DABSO and alkyl potassium trifluoroborate to synthesize polyfluoroaryl sulfone skeleton in one step under visible light catalysis. Visible light is a natural resource that is abundant, green, pollution-free and recyclable. The use of visible light to prepare polyfluoroaryl-substituted sulfone compounds has the advantages of green energy saving and environmental protection, and meets the requirements of green chemistry and sustainable development.

[0030] 2. The present application does not need to add additional reducing agents or bases, and the operation is simple, and the reaction system is relatively simple.

[0031] 3. The synthetic method provided by the application can be carried out at room temperature without high temperature, and the reaction condition is mild.

[0032] 4. The synthetic method provided by the application can obtain corresponding products with excellent yield for substrates containing methyl, isopropyl, tert-butyl, phenyl, benzyl and other polyfluoroarene, and shows excellent functional group tolerance, wide application range, excellent catalytic synthesis value and industrial application potential, and provides a new method for realizing synthesis of polyfluoroaryl-substituted sulfone compounds. BRIEF DESCRIPTION OF DRAWINGS

[0033] The drawings described herein are used to provide further understanding of the embodiments of the application, form a part of the application, and do not constitute limitations on the embodiments of the application. In the drawings:

[0034] embodiments NMR hydrogen spectrum of the polyfluoroaryl-substituted sulfone compound 4aa provided for the embodiment.

[0035] As NMR carbon spectrum of the polyfluoroaryl-substituted sulfone compound 4aa provided for the embodiment.

[0036] shown NMR fluorine spectrum of the polyfluoroaryl-substituted sulfone compound 4aa provided for the embodiment.

[0037] in NMR hydrogen spectrum of the polyfluoroaryl-substituted sulfone compound 4ba provided for the embodiment.

[0038] the NMR carbon spectrum of the polyfluoroaryl-substituted sulfone compound 4ba provided for the embodiment.

[0039] above NMR fluorine spectrum of the polyfluoroaryl-substituted sulfone compound 4ba provided for the embodiment.

[0040] embodiments NMR hydrogen spectrum of the polyfluoroaryl-substituted sulfone compound 4ca provided for the embodiment.

[0041] Figure 1 NMR carbon spectrum of the polyfluoroaryl-substituted sulfone compound 4ca provided for the embodiment.

[0042] Figure 2 NMR fluorine spectrum of the polyfluoroaryl-substituted sulfone compound 4ca provided for the embodiment.

[0043] Figure 3 NMR hydrogen spectrum of the polyfluoroaryl-substituted sulfone compound 4da provided for the embodiment.

[0044] Figure 4The nuclear magnetic carbon spectrum of the polyfluoro aryl substituted sulfone compound 4da provided for the example.

[0045] Figure 5 The nuclear magnetic fluorine spectrum of the polyfluoro aryl substituted sulfone compound 4da provided for the example.

[0046] Figure 6 The nuclear magnetic hydrogen spectrum of the polyfluoro aryl substituted sulfone compound 4ab provided for the example.

[0047] Figure 7 The nuclear magnetic carbon spectrum of the polyfluoro aryl substituted sulfone compound 4ab provided for the example.

[0048] Figure 8 The nuclear magnetic fluorine spectrum of the polyfluoro aryl substituted sulfone compound 4ab provided for the example.

[0049] Figure 9 The nuclear magnetic hydrogen spectrum of the polyfluoro aryl substituted sulfone compound 4ea provided for the example.

[0050] Figure 10 The nuclear magnetic carbon spectrum of the polyfluoro aryl substituted sulfone compound 4ea provided for the example.

[0051] Figure 11 The nuclear magnetic fluorine spectrum of the polyfluoro aryl substituted sulfone compound 4ea provided for the example.

[0052] Figure 12 The nuclear magnetic fluorine spectrum of the polyfluoro aryl substituted sulfone compound 4ea provided for the example. DETAILED DESCRIPTION

[0053] In order to make the objectives, technical solutions and advantages of the present application clearer, further detailed description will be given to the present application in combination with the examples and drawings, the illustrative embodiments of the present application and the description thereof are only used to explain the present application, and do not limit the present application.

[0054] The present application provides a polyfluoro aryl substituted sulfone compound, and the chemical structural formula is as follows:

[0055]

[0056] Wherein:

[0057] OR1 includes one of methoxy, isopropoxy, t-butoxy, phenoxy, benzyloxy and the alkoxyl derived from menthol, fructose diketone and ginger ketone;

[0058] R2 includes one of cyano, trifluoromethyl and ketone carbonyl;

[0059] R3 includes one of tert-butyl, isopropyl, ethyl, n-butyl, cyclobutyl, cyclopentyl, cyclohexyl, substituted or unsubstituted benzyl.

[0060] The present application provides a synthesis method of a polyfluoroaryl-substituted sulfone compound, for preparing the polyfluoroaryl-substituted sulfone compound, comprising the steps of:

[0061] In an inert atmosphere, under the action of a photocatalyst, the reactant is subjected to a photocatalytic reaction under visible light irradiation in a solvent to obtain the polyfluoroaryl-substituted sulfone compound.

[0062] The reactant comprises a polyfluoroarene compound, DABSO, and potassium alkyl trifluoroborate.

[0063] The present application uses a cheap and readily available SO2 / SO2 substitute such as DABSO as a sulfonyl source to realize the multi-component sulfur dioxide insertion and coupling process of polyfluoroarene under mild conditions, which can alleviate the problems of traditional synthesis of polyfluoroaryl sulfone compounds, such as harsh reaction conditions, complicated steps, poor functional group compatibility, or dependence on sodium sulfinic acid, and realizes efficient and precise construction of polyfluoroaryl sulfone compounds. However, so far, a three-component tandem synthesis method of polyfluoroaryl sulfone compounds has not been realized.

[0064] In some embodiments, the reaction formula of the synthesis method of the polyfluoroaryl-substituted sulfone compound is as follows:

[0065]

[0066] In some embodiments, the solvent comprises dimethyl sulfoxide (DMSO).

[0067] Preferably, the photocatalytic reaction is started under the irradiation of 5W blue light LEDs.

[0068] Preferably, the synthesis method further comprises the steps of:

[0069] After the photocatalytic reaction is completed, the polyfluoroaryl-substituted sulfone compound is obtained through purification treatment.

[0070] More preferably, after the photocatalytic reaction is completed, the reaction system is quenched with a saturated aqueous sodium chloride solution, extracted with ethyl acetate three times, the organic phase is combined, dried with anhydrous sodium sulfate, the solvent is removed with a rotary evaporator, adsorbed on silica gel, and the polyfluoroaryl-substituted sulfone compound is obtained through simple column chromatography.

[0071] In some embodiments, the chemical structural formula of the polyfluoroarene compound is:

[0072]

[0073] and / or, the chemical structural formula of the potassium alkyl trifluoroborate is:

[0074] R3-BF3K

[0075] and / or, the photocatalyst comprises [Ir(dtbbpy)[dF(CF3)ppy]2]PF6; the chemical structural formula of [Ir(dtbbpy)[dF(CF3)ppy]2]PF6 is as follows:

[0076]

[0077] In some embodiments, the molar ratio of the polyfluoroarene compound, the DABSO, the potassium alkyltrifluoroborate and the photocatalyst is 1:(1-3):(1-3):(0.01-0.03).

[0078] More preferably, the molar ratio of the polyfluoroarene compound, the DABSO, the potassium alkyltrifluoroborate and the photocatalyst is 1:1:1.5:0.015, and the reaction is carried out at the molar ratio to obtain a higher yield with a more optimal atomic utilization rate, which has atomic economy.

[0079] In some embodiments, the amount of the polyfluoroarene compound and the solvent is 0.2 mmol:(1-3) ml.

[0080] More preferably, the amount of the polyfluoroarene compound and the solvent is 0.2 mmol:2 ml, and the reaction system has a concentration of 0.1 M, and the reaction is carried out at the amount ratio to obtain a higher yield with a more optimal reaction rate.

[0081] In some embodiments, the reaction temperature in the photocatalytic reaction is 18-40℃.

[0082] More preferably, the reaction temperature is 25℃.

[0083] In some embodiments, the reaction time in the photocatalytic reaction is 24-96 h.

[0084] More preferably, the reaction time is 24 h.

[0085] The polyfluoroaryl-substituted sulfone compound provided by the application has the following chemical structure:

[0086] The application can synthesize the following polyfluoroaryl-substituted sulfone compound:

[0087]

[0088] 4ea is the corresponding ester containing menthol structure. Menthol can be used as a flavoring agent in toothpaste, perfume, beverage and candy, etc. It is used as a stimulant in medicine, acting on the skin or mucous membrane, and has a cooling and itching effect. It can be used as a wind expelling drug for internal use, and used for headache and inflammation of the nose, throat and throat. The present application can modify natural products or drug active molecules such as menthol to synthesize multi-fluorine aryl substituted sulfone compounds such as 4ea.

[0089] Embodiment

[0090] The present embodiment provides a multi-fluorine aryl substituted sulfone compound, a reaction general formula and a method as follows, which is carried out under the protection of nitrogen atmosphere.

[0091]

[0092] Under the protection of nitrogen atmosphere, a photocatalyst [Ir(dtbbpy)[dF(CF3)ppy]2]PF6(1.5 mol%) was added to the reaction tube, a solvent dimethyl sulfoxide (DMSO, 2 mL), a multi-fluorine aromatic compound 1 (0.2 mmol), DABSO 2 (0.2 mmol), potassium alkyl trifluoroborate 3 (0.3 mmol), and stirred at room temperature for 24 h under the irradiation of 5W blue light LEDs. The reaction system was quenched with saturated brine solution, extracted with ethyl acetate three times, the organic phase was combined, dried with anhydrous sodium sulfate, and the solvent was removed by rotary evaporator. The multi-fluorine aryl substituted sulfone compound 4 was obtained by simple column chromatography.

[0093] By selecting different multi-fluorine aromatic compounds 1, the multi-fluorine aryl substituted sulfone compounds were prepared by the above synthesis method, and each multi-fluorine aryl substituted sulfone compound was named as 4aa, 4ba, 4ca, 4da, 4ab, 4ea, and the specific structural formula was as shown below:

[0094]

[0095] I. Structure characterization

[0096] 1. The multi-fluorine aryl substituted sulfone compounds obtained in the embodiment were subjected to nuclear magnetic resonance detection, and the results were as shown in Figure 13

[0097] The nuclear magnetic resonance spectrum of 4aa is as shown in Figure 14 The yield is 99%. 1 HNMR (500 MHz, CDCl3) δ 4.04 (s, 3H), 1.46 (s, 9H). 13 ​C NMR (151 MHz, CDC13) δ 159.00, 145.48 (dm, J = 258.2 Hz), 144.78 (dm, J = 259.7 Hz), 118.46 (t, J = 14.5 Hz), 118.17 (t, J = 17.0 Hz), 63.37, 54.06, 22.90. 19 F NMR (565 MHz, CDC13) δ -130.51 - -130.60 (m), -136.11 - -136.20 (m). HRMS (ESI-TOF) (m / z): Calcd for C 12 H 12 F4Na04S ([M + Na] + ), 351.0285; found, 351.0284.

[0098] The nuclear magnetic resonance spectrum of 4ba is shown in Figure 15 Figure 1, with a yield of 99%. 1 H NMR (500 MHz, CDC13) δ 7.47 (t, J = 8.0 Hz, 2H), 7.34 (t, J = 7.5 Hz, 1H), 7.30 - 7.21 (m, 2H), 1.48 (s, 9H). 13 C NMR (151 MHz, CDC13) δ 157.05, 150.07, 145.45 (dm, J = 262.7 Hz), 144.33 (dm, J = 258.2 Hz), 130.03, 127.24, 121.28, 120.18 (t, J = 18.4 Hz), 117.52 (t, J = 14.0 Hz), 63.49, 22.97. 19 F NMR (565 MHz, CDC13) δ -129.76 - -130.39 (m), -135.34 - -135.77 (m). HRMS (ESI-TOF) (m / z): Calcd for C 17 H 14 F4Na04S ([M + Na] + ) 413.0441, found, 413.0439.

[0099] The nuclear magnetic resonance spectrum of 4ca is shown in Figure 16 Figure 1, with a yield of 63%. 1 H NMR (500 MHz, CDC13) δ 1.47 (s, 9H). 13C NMR (151 MHz, CDC13) δ 148.51 - 148.11 (m), 146.86 - 146.29 (m), 144.69 - 144.29 (m), 121.87 (t, J = 15.0 Hz), 106.16, 63.66, 22.74. 19 F NMR (565 MHz, CDC13) δ -128.11 - -128.27 (m), -128.29 - -128.42 (m).

[0100] The nuclear magnetic resonance spectrum of 4da is shown in Figure 17 with a yield of 68%. 1 HNMR (500 MHz, CDC13) δ 1.48 (s, 9H). 13 C NMR (151 MHz, CDC13) δ 144.38 (dm, J = 250.6 Hz), 140.23 (dm, J = 273.3 Hz), 128.24 (t, J = 13.2 Hz), 63.45, 22.70. 19 F NMR (565 MHz, CDC13) δ -85.29 - -86.73 (m), -132.62 - -132.95 (m).

[0101] The nuclear magnetic resonance spectrum of 4ab is shown in Figure 18 with a yield of 83%. 1 HNMR (500 MHz, CDC13) δ 7.38 (t, J = 10.0 Hz, 1H), 7.34 (t, J = 7.5 Hz, 2H), 7.29 - 7.27 (m, 2H), 4.59 (s, 2H), 4.00 (s, 3H). 13 C NMR (151 MHz, CDC13) δ 158.70, 144.43 (dm, J = 256.7 Hz), 130.66, 129.82, 129.17, 125.83, 120.15 (t, J = 14.7 Hz), 117.66 (t, J = 16.7 Hz), 63.84, 53.86. 19 F NMR (565 MHz, CDC13) δ -134.47 - -134.86 (m), -135.94 - -136.17 (m). HRMS (ESI-TOF) (m / z): Calcd for C 15 H 10 F4NaO4S ([M+Na] + ), 385.0128; found, 385.0117.

[0102] The nuclear magnetic resonance spectrum of 4ea is shown in Figure 19 Figures 1-18 Figures 1-3 Figures 4-6 Figures 7-9 Figures 10-12 Figures 13-15 Figures 16-18Yield 99%. 1 H NMR (500 MHz, CDC13) δ 5.03 (td, J = 11.0, 4.5 Hz, 2H), 2.21 - 2.13 (m, 1H), 1.97 (m, 1H), 1.74 (m, 2H), 1.60 - 1.36 (m, 12H), 1.20 - 1.04 (m, 2H), 0.96 (d, J = 6.5 Hz, 3H), 0.93 (d, J = 7.0 Hz, 3H), 0.82 (d, J = 7.0 Hz, 3H). 13 C NMR (151 MHz, CDC13) δ 157.98, 145.27 (dm, J = 267.2 Hz), 144.22 (dm, J = 259.7 Hz), 119.09 (t, J = 18.4 Hz), 117.69 (t, J = 14.5 Hz), 78.60, 63.11, 46.80, 40.51, 33.95, 31.49, 25.93, 23.04, 22.71, 21.87, 20.71, 15.80. 19 F NMR (565 MHz, CDC13) δ -130.56 - -130.68 (m), -136.44 - -137.41 (m). HRMS (ESI-TOF) (m / z): Calcd for C 21 H 28 F4NaO4S ([M+Na] + ), 475.1537; found, 475.1532.

[0103] The above specific embodiments, the purpose of the present application, technical solutions and beneficial effects are further described in detail, it should be understood that the above description is only a specific embodiment of the present application, and is not used to limit the protection scope of the present application, any modification, equivalent replacement, improvement, etc. made within the spirit and principles of the present application should be included in the protection scope of the present application.

Claims

1. A method for synthesizing polyfluoroaryl substituted sulfone compounds, characterized in that, Including the following steps: In an inert atmosphere, under the action of a photocatalyst, the reactants undergo a photocatalytic reaction in a solvent under visible light irradiation to prepare polyfluoroaryl substituted sulfone compounds. The reactants include polyfluoroaromatic compounds, bis(sulfur dioxide)-1,4-diazabicyclo[2.2.2]octane adducts, and alkyl trifluoroborate potassium; The chemical structural formula of the polyfluoroaromatic compound is: The chemical structural formula of the potassium trifluoroborate alkyl is as follows: R3-BF3K; The photocatalyst is [Ir(dtbbpy)(dF(CF3)ppy]2]PF6; the chemical structural formula of [Ir(dtbbpy)(dF(CF3)ppy]2]PF6 is: The molar ratio of the polyfluoroaromatic compound, the bis(sulfur dioxide)-1,4-diazabicyclo[2.2.2]octane adduct, the alkyl trifluoroborate potassium, and the photocatalyst is 1:(1-3):(1-3):(0.01-0.03); The chemical structural formulas of the obtained polyfluoroaryl substituted sulfone compounds are as follows: in: OR1 is selected from one of methoxy, isopropoxy, tert-butoxy, phenoxy, benzyloxy, and alkoxy derived from menthol, fructose diacetone, and gingerone; R2 is selected from one of cyano, trifluoromethyl, and ketone carbonyl groups; R3 is selected from one of tert-butyl, isopropyl, ethyl, n-butyl, cyclobutyl, cyclopentyl, cyclohexyl, substituted or unsubstituted benzyl.

2. The method for synthesizing a polyfluoroaryl substituted sulfone compound according to claim 1, characterized in that, The ratio of the polyfluoroaromatic compound to the solvent is 0.2 mmol:(1-3) ml.

3. The method for synthesizing a polyfluoroaryl substituted sulfone compound according to claim 1, characterized in that, In the photocatalytic reaction, the reaction temperature is 18℃~40℃.

4. The method for synthesizing a polyfluoroaryl substituted sulfone compound according to claim 1, characterized in that, In the photocatalytic reaction, the reaction time is 24h to 96h.

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