Method for realizing sulfo-sulfonate alkylation based on micro-flow field technology

Abstract

The invention belongs to the field of organic chemical synthesis, and relates to a method for realizing thiosulfonate alkylation based on a micro-flow field technology. The preparation method comprises the following steps: mixing a thiobenzene sulfonate compound 1 with a compound 2, an iron catalyst, a ligand and a first solvent to obtain a mixed solution; and pumping the mixed solution into a micro-flow field reactor of the micro-flow field reaction device to carry out photoreaction, thereby obtaining the sulfo-product 3. According to the method, alkane with low reaction activity is activated in the mode that the iron catalyst which is low in price and easy to obtain is excited to generate free radicals under purple light irradiation, and the alkane and thiosulfonate are subjected to cross coupling to achieve the thioalkylation modification reaction at the room temperature. According to the method, the condition is mild, an exogenous oxidant and an expensive transition metal complex do not need to be added, meanwhile, the reaction process is enhanced through the micro-flow field technology, the reaction efficiency is improved, the reaction time is greatly shortened, and a powerful foundation is laid for large-scale preparation of related products.

Description

Technical Field

[0001] The present invention belongs to the field of organic chemical synthesis and relates to a method for realizing the alkylation of thiosulfonates based on microfluidic technology. Background Art

[0002] As a core structural unit of drug molecules (such as olaparib), natural products, and functional materials, the efficient construction of the C-S bond in sulfur-containing compounds has always been a focus issue in the field of organic synthesis. Although significant progress has been made in traditional transition metal catalysis and electrochemical oxidative coupling, in the context of green chemistry and sustainable manufacturing, photocatalytic technology is emerging as an innovative path for C-S bond construction due to its advantages such as clean energy drive (photon utilization efficiency > 35%), atom economy (no need for external oxidants), and mild conditions (room temperature and atmospheric pressure). Microfluidic technology realizes a specific surface area of the reaction system exceeding 10 3 m 2 / m 3 through the design of sub-millimeter channels (characteristic scale 200 - 500 μm), which improves the mass transfer coefficient (kLa) by 2 - 3 orders of magnitude and the heat transfer efficiency by more than 80% compared with traditional batch reactors, effectively solving the problem of mass transfer limitation caused by the diffusion boundary layer in macroscopic reactors. This system can precisely control key parameters such as flow rate and pressure, and combined with the regulation of residence time distribution, the conversion stability of fast processes such as free radical chain reactions can be improved to a relative standard deviation (RSD) < 1.5%. Summary of the Invention

[0003] The technical problem to be solved by the present invention is to provide a method for realizing the alkylation of thiosulfonates under the synergistic catalysis of microfluidic light / iron in view of the deficiencies of the prior art, and to strengthen the process through the advantages of microfluidic technology, so as to solve the problems existing in the prior art such as long reaction time, low reaction yield, cumbersome steps, and inability to be scaled up on a large scale.

[0004] To solve the above technical problems, the technical solution adopted by the present invention is as follows:

[0005] The present invention discloses a method for realizing the alkylation of thiosulfonates based on microfluidic technology. A thiosulfonic acid phenyl ester compound 1 is mixed with a compound 2, an iron catalyst, a ligand, and a first solvent to obtain a mixed solution; the mixed solution is pumped into a microfluidic reactor of a microfluidic reaction device for a photoreaction to obtain a thio product 3;

[0006] Among them, the structure of the thiosulfonic acid phenyl ester compound 1 is shown in Formula 1, the structure of the compound 2 is shown in Formula 2, and the structure of the thio product 3 is shown in Formula 3:

[0007]

[0008] Among them,

[0009] R is selected from substituted or unsubstituted phenyl;

[0010] R1 and R2 are independently selected from substituted or unsubstituted C1-C6 alkyl; wherein, R1 and R2 can be connected through C or O to form a 3-8 membered ring;

[0011] Wherein, the substitution is selected from being substituted by 1 to 5 identical or different substituents; the substituents are C1-C4 alkyl, C1-C4 alkoxy or halogen.

[0012] In some embodiments, R is selected from substituted or unsubstituted phenyl;

[0013] R1 and R2 are independently selected from substituted or unsubstituted C1-C6 alkyl; wherein, R1 and R2 can be connected through C or O to form a 5-7 membered ring;

[0014] Wherein, the substituents are C1-C4 alkyl, C1-C2 alkoxy or halogen.

[0015] In some embodiments, preferably, R is selected from substituted or unsubstituted phenyl;

[0016] R1 and R2 are independently selected from substituted or unsubstituted C1-C6 alkyl; wherein, R1 and R2 can be connected through C or O to form a 5-7 membered ring;

[0017] Wherein, the substituents are methyl, tert-butyl, methoxy or bromine.

[0018] In some embodiments, further preferably, the thiosulfonate compound 1 is selected from any one of the following structures:

[0019]

[0020] In some embodiments, further preferably, the compound 2 is selected from any one of the following structures:

[0021]

[0022] In some embodiments, preferably, an iron catalyst, a ligand and a second solvent are mixed, stirred under an inert gas protection for complexation, the solvent is removed, and recrystallization is carried out to obtain an iron catalyst / ligand complex; the thiosulfonate compound 1, the compound 2, the iron catalyst / ligand complex and a first solvent are mixed to obtain a mixed solution; the mixed solution is pumped into a microfluidic reactor of a microfluidic reaction device for a photoreaction to obtain a thio product 3.

[0023] In some embodiments, the iron catalyst is any one or a combination of several of ferric chloride, iron(III) trifluoromethanesulfonate, ferrous chloride, ferrous acetylacetonate, iron(III) acetylacetonate, ferrous acetate, iron(III) sulfate heptahydrate, ferrocene, ferrous oxalate dihydrate, ferrous sulfate, iron(III) bromide, and 1,1'-bis(diphenylphosphino)ferrocene; and / or, the ligand is any one or a combination of two of tetrabutylammonium chloride and tetraethylammonium chloride; and / or, the first solvent is any one or a combination of several of acetonitrile, dimethyl sulfoxide, methanol, N,N-dimethylformamide, ethanol, N,N-dimethylacetamide, trifluoroethanol, ethyl acetate, dichloromethane, isopropanol, acetone, 1,2-dichloroethane, p-xylene, hexafluoroisopropanol, toluene, and water; and / or, the second solvent is any one or a combination of several of acetonitrile, dimethyl sulfoxide, methanol, N,N-dimethylformamide, ethanol, N,N-dimethylacetamide, trifluoroethanol, ethyl acetate, dichloromethane, isopropanol, acetone, 1,2-dichloroethane, p-xylene, hexafluoroisopropanol, toluene, and water.

[0024] In some embodiments, preferably, the iron catalyst is ferric chloride, iron(III) trifluoromethanesulfonate, or ferrous acetate, and more preferably ferric chloride.

[0025] In some embodiments, preferably, the ligand is tetrabutylammonium chloride.

[0026] In some embodiments, preferably, the first solvent is acetonitrile, methanol, ethyl acetate, dichloromethane, or acetone, and more preferably acetonitrile.

[0027] In some embodiments, preferably, the second solvent is acetonitrile, methanol, N,N-dimethylformamide, dichloromethane, or acetone, and more preferably acetonitrile.

[0028] In some embodiments, the molar ratio of the iron catalyst to the ligand is 1.0:(1.0 - 2.5); and / or, the complexation is carried out at room temperature; and / or, the time of complexation is 10 min to 2 h; and / or, the inert gas is nitrogen.

[0029] In some embodiments, preferably, the molar ratio of the iron catalyst to the ligand is 1.0:(1.0 - 1.5), and more preferably 1.0:1.0.

[0030] In some embodiments, preferably, the time of complexation is 10 min to 1 h, more preferably 10 min to 40 min, and even more preferably 30 min.

[0031] Wherein, there is no special requirement for the amount of the second solvent, and it is only necessary to dissolve or disperse the raw materials evenly.

[0032] In some embodiments, the molar ratio of the thiosulfonate compound 1, the compound 2, and the iron catalyst / ligand complex is 1.0:(2.0 - 20.0):(0.05 - 1.0).

[0033] In some embodiments, preferably, the molar ratio of the thiosulfonate compound 1, the compound 2, and the iron catalyst / ligand complex is 1.0:(2.0 - 8.0):(0.05 - 0.5), more preferably 1.0:(4.0 - 6.0):(0.10 - 0.2), and even more preferably 1.0:5.0:0.1.

[0034] In some embodiments, in the mixed solution, the concentration of the thiosulfonate compound 1 is 0.01 mmol / mL - 0.20 mmol / mL.

[0035] In some embodiments, preferably, in the mixed solution, the concentration of the thiosulfonate compound 1 is 0.05 mmol / mL - 0.15 mmol / mL.

[0036] In some embodiments, more preferably, in the mixed solution, the concentration of the thiosulfonate compound 1 is 0.05 mmol / mL - 0.10 mmol / mL.

[0037] In some embodiments, even more preferably, in the mixed solution, the concentration of the thiosulfonate compound 1 is 0.10 mmol / mL.

[0038] In some embodiments, for the photoreaction, the reaction temperature is room temperature; and / or, for the photoreaction, the residence time in the microfluidic reactor is 30 s - 1 h.

[0039] In some embodiments, preferably, for the photoreaction, the residence time in the microfluidic reactor is 10 min - 30 min.

[0040] In some embodiments, more preferably, for the photoreaction, the residence time in the microfluidic reactor is 20 min.

[0041] In some embodiments, for the photoreaction, the wavelength of the light is 360 nm - 600 nm.

[0042] In some embodiments, preferably, for the photoreaction, the wavelength of the light is 360 nm - 450 nm.

[0043] In some embodiments, more preferably, for the photoreaction, the wavelength of the light is 390 nm.

[0044] In some embodiments, the microfluidic reaction device includes a connecting pipeline, a feeding pump, a microfluidic reactor, a light source, and a receiver; wherein, the feeding pump, the microfluidic reactor, and the receiver are connected in series in sequence through the connecting pipeline; the light source is located outside the microfluidic reactor, and its light illumination range covers the microfluidic reactor.

[0045] Among them, the feeding pump is of the model Baoding Leifu Fluid Technology Co., Ltd, TYD01-01-CE type.

[0046] Among them, the microfluidic reactor is a tubular reactor, the pore channel material is perfluoroalkoxy alkane (PFA, a transparent material), the inner diameter of the pipeline is 0.6 - 2.0 mm, preferably 0.6 - 1.0 mm, and further preferably 1.0 mm.

[0047] Among them, the light source is an LED lamp, the power of the LED lamp is 10W - 60W, preferably 20W - 60W, further preferably 30W - 50W, and even further preferably 40W.

[0048] The thio product shown in Formula 3 provided by the present invention can be used to synthesize and design specific site modifications of natural products and drug molecules and can be applied to multiple fields such as new drug research and development, materials, etc. At the same time, the present invention also provides a new idea for the industrial large-scale production of high-value-added sulfur-containing compounds.

[0049] Beneficial effects:

[0050] (1) The present invention innovatively couples visible light catalysis and microfluidic technology to achieve efficient construction of C(sp 3 )-S bonds without an external oxidant. This technology breaks through the risk of side reactions caused by strong oxidants and realizes gram-scale amplification through modular equipment, providing an industrial example for the green synthesis of sulfur-containing drug molecules and functional materials.

[0051] (2) The present invention does not require the use of expensive photocatalysts and strong oxidants with potential safety risks. Inert alkanes can be activated through cheap and easily available iron catalysts, avoiding cumbersome steps and reducing the synthesis difficulty and cost.

[0052] (3) The iron catalyst / ligand complex used in the synthesis of the present invention has a short synthesis step and simple post-treatment, and has higher reaction activity and substrate scope compared with traditional iron catalysts.

[0053] (4) The present invention uses microfluidic technology to strengthen the reaction process, shortening the reaction time while improving the reaction selectivity, and being easy to scale up.

[0054] (5) The reaction conditions involved in the present invention are mild, the substrate scope is wide, and the product yield is relatively high (up to 75% - 95%).

[0055] (6) The present invention uses an inexpensive and readily available iron catalyst to activate alkanes with low reaction activity by generating free radicals under ultraviolet light irradiation, and cross-couples with thiosulfonates to achieve thioalkylation modification reaction at room temperature. This method has mild conditions, does not require the addition of exogenous oxidants and expensive transition metal complexes, and at the same time strengthens the reaction process through microfluidic technology, improves the reaction efficiency, greatly shortens the reaction time, and lays a strong foundation for the large-scale preparation of related products. BRIEF DESCRIPTION OF THE DRAWINGS

[0056] The following further specifically describes the present invention in conjunction with the drawings and specific embodiments, and the above and / or other advantages of the present invention will become clearer.

[0057] Figure 1 It is a microfluidic reaction device diagram used in the embodiments of the present invention.

[0058] Figure 2 It is the 1H nuclear magnetic resonance spectrum of product 3aa in Example 1.

[0059] Figure 3 It is the 13C nuclear magnetic resonance spectrum of product 3aa in Example 1. DETAILED DESCRIPTION OF THE EMBODIMENTS

[0060] According to the following embodiments, the present invention can be better understood. However, those skilled in the art can easily understand that the content described in the embodiments is only used to illustrate the present invention, and should not and will not limit the present invention described in detail in the claims.

[0061] In the following embodiments, the experimental methods described are all conventional methods unless otherwise specified; the reagents and materials described are all available from commercial sources unless otherwise specified.

[0062] 1. The microfluidic reaction device diagram used in the embodiments of the present invention is as Figure 1 shown. The microfluidic reaction device includes a connecting pipeline, a feed pump, a microfluidic reactor, a light source, and a receiver; among them, the feed pump, the microfluidic reactor, and the receiver are sequentially connected in series through the connecting pipeline; the light source is located outside the microfluidic reactor, and its light irradiation range covers the microfluidic reactor.

[0063] Among them, the feed pump has a model of Baoding Leifu Fluid Technology Co., Ltd, TYD01 - 01 - CE type.

[0064] Among them, the microfluidic reactor is a tubular reactor, the pore material is perfluoroalkoxy alkane (PFA, a transparent material), the inner diameter of the pipeline is 1.0 mm, and the total retention volume of the microfluidic reactor is 2.0 mL.

[0065] Among them, the light source is an LED lamp, the wavelength of the light is 390 nm, and the power of the LED lamp is 40 W.

[0066] 2. The specific preparation method of the (tetrabutylammonium chloride) iron(III) chloride complex used in the embodiments of the present invention is as follows:

[0067] FeCl3 + TBACl → TBAFeCl4

[0068] Add FeCl3 (162.3 mg, 1.0 mmol), tetrabutylammonium chloride (276.5 mg, 1.0 mmol) and 1.0 mL of acetonitrile to a 20 mL round-bottom flask respectively. Stir the resulting mixture under a nitrogen atmosphere at room temperature for 30 minutes, then distill under reduced pressure, and recrystallize with petroleum ether / ethyl acetate to obtain the product (tetrabutylammonium chloride) iron(III) chloride complex (TBAFCl4, yield 99%).

[0069] Example 1:

[0070]

[0071] Weigh S-phenylthiophenyl sulfone (0.2 mmol, 1.0 equiv.), 1,4-dioxane (1.0 mmol, 5.0 equiv.), and (tetrabutylammonium chloride) iron(III) chloride complex (0.02 mmol, 0.1 equiv.) in sequence, add the solvent acetonitrile and stir well to dissolve it to prepare a 2.0 mL mixed solution. Pump the mixed solution into a microfluidic reactor with a total retention volume of 2.0 mL and a pipeline inner diameter of 1.0 mm, and carry out a photoreaction at room temperature (the wavelength of the light is 390 nm). The reaction residence time in the microfluidic reactor is 20 minutes. After the reaction is completed, collect the reaction solution and extract it with ethyl acetate and saturated brine (3 × 25 mL). Combine the organic layers, dry with anhydrous sodium sulfate, distill off the solvent under reduced pressure, and obtain the product 3aa, 33.8 mg, with a separation yield of 86% through silica gel column chromatography (petroleum ether:ethyl acetate = 20:1).

[0072] The characterization data of the product 3aa are as follows: 1¹H NMR (400 MHz, Chloroform-d) δ 7.53–7.48 (m, 2H), 7.34–7.23 (m, 3H), 5.14–5.10 (m, 1H), 4.26–4.20 (m, 1H), 4.00–3.96 (m, 1H), 3.75–3.70 (m, 2H), 3.70–3.65 (m, 2H). 13 ¹³C NMR (101 MHz, Chloroform-d) δ 134.0, 131.6, 129.0, 127.4, 83.3, 70.0, 66.5, 63.8. HRMS (ESI) m / z: calcd for C 10 H 13 O₂S [M+H] + : 197.0631, found: 197.0642. The ¹H NMR spectrum of product 3aa is as shown in Figure 2 shown, and the ¹³C NMR spectrum of product 3aa is as shown in Figure 3 shown.

[0073] Example 2:

[0074]

[0075] Weigh in sequence S-phenylthiophenyl sulfone (0.2 mmol, 1.0 equiv.), cyclohexane (1.0 mmol, 5.0 equiv.), (tetrabutylammonium chloride) iron(III) chloride complex (0.02 mmol, 0.1 equiv.), add solvent acetonitrile and stir well to dissolve, and prepare a 2.0 mL mixed solution. Pump the mixed solution into a microfluidic reactor with a total retention volume of 2.0 mL and an inner pipe diameter of 1.0 mm, and carry out a photoreaction at room temperature (the wavelength of light is 390 nm). The residence time of the reaction in the microfluidic reactor is 20 minutes. After the reaction is completed, collect the reaction solution and extract it with ethyl acetate and saturated brine (3 × 25 mL). Combine the organic layers, dry with anhydrous sodium sulfate, distill off the solvent under reduced pressure, and obtain product 3ab, 35.4 mg, with a separation yield of 92%.

[0076] The characterization data of product 3ab are as follows: 1 ¹H NMR (400 MHz, Chloroform-d) δ 7.36–7.33 (m, 2H), 7.30–7.27 (m, 3H), 3.34–3.29 (m, 1H), 1.85–1.76 (m, 2H), 1.66–1.58 (m, 4H), 1.56–1.40 (m, 4H). 1313C NMR (101 MHz, Chloroform-d) δ 134.9, 129.5, 129.2, 127.8, 46.5, 33.4, 25.5, 25.0. HRMS (ESI) m / z: calcd for C 12 H 17 S[M + H] + : 193.1045, found: 193.1049.

[0077] Example 3:

[0078]

[0079] Weigh successively S-phenylthiophenyl sulfone (0.2 mmol, 1.0 equiv.), tetrahydrofuran (1.0 mmol, 5.0 equiv.), (tetrabutylammonium chloride) iron(III) chloride complex (0.02 mmol, 0.1 equiv.), add the solvent acetonitrile and stir well to dissolve it, and prepare a 2.0 mL mixed solution. Pump the mixed solution into a microfluidic reactor with a total retention volume of 2.0 mL and a pipe inner diameter of 1.0 mm, and carry out a photoreaction at room temperature (the wavelength of light is 390 nm). The reaction residence time in the microfluidic reactor is 20 minutes. After the reaction is completed, collect the reaction solution and extract it with ethyl acetate and saturated brine (3 × 25 mL). Combine the organic layers, dry with anhydrous sodium sulfate, distill off the solvent under reduced pressure, and obtain the product 3ac by silica gel column chromatography (petroleum ether: ethyl acetate = 20:1). The separation yield is 89%.

[0080] The characterization data of the product 3ac are as follows: 1 1H NMR (400 MHz, Chloroform-d) δ 7.46–7.43 (m, 2H), 7.38–7.34 (m, 2H), 7.31–7.27 (m, 1H), 5.32 (t, J = 2.4 Hz, 1H), 3.95–3.90 (m, 1H), 3.89–3.84 (m, 1H), 2.27–2.21 (m, 1H), 2.06–2.01 (m, 2H), 1.97–1.91 (m, 1H). 13 13C NMR (101 MHz, Chloroform-d) δ 133.4, 130.0, 129.6, 128.0, 93.0, 68.6, 33.1, 23.2. HRMS (ESI) m / z: calcdfor C 10 H 13 OS[M + H] + : 181.0682, found: 181.0691.

[0081] Example 4:

[0082]

[0083] Weigh in sequence S-phenylthiophenyl sulfone (0.2 mmol, 1.0 equiv.), cyclopentane (1.0 mmol, 5.0 equiv.), (tetrabutylammonium chloride) iron(III) chloride complex (0.02 mmol, 0.1 equiv.), add the solvent acetonitrile and stir well to dissolve it, and prepare a 2.0 mL mixed solution. Pump the mixed solution into a microfluidic reactor with a total retention volume of 2.0 mL and an inner pipe diameter of 1.0 mm, and carry out a photoreaction at room temperature (the wavelength of light is 390 nm). The residence time of the reaction in the microfluidic reactor is 20 minutes. After the reaction is completed, collect the reaction solution and extract it with ethyl acetate and saturated brine (3 × 25 mL). Combine the organic layers, dry with anhydrous sodium sulfate, distill off the solvent under reduced pressure, and obtain the product 3ad, 30.7 mg, with a separation yield of 86%.

[0084] The characterization data of the product 3ad are as follows: 1 H NMR (400 MHz, Chloroform-d) δ 7.37–7.33 (m, 2H), 7.30–7.27 (m, 3H), 3.41–3.37 (m, 1H), 1.98–1.91 (m, 2H), 1.87–1.79 (m, 2H), 1.73–1.63 (m, 4H). 13 C NMR (101 MHz, Chloroform-d) δ 134.4, 129.5, 129.2, 127.8, 49.7, 33.0, 24.0. HRMS (ESI) m / z: calcd for C 11 H 15 S[M+H] + : 179.0889, found: 179.0896.

[0085] Example 5:

[0086]

[0087] Weigh successively S-phenylthiophenyl sulfone (0.2 mmol, 1.0 equiv.), cycloheptane (1.0 mmol, 5.0 equiv.), and (tetrabutylammonium chloride) iron(III) chloride complex (0.02 mmol, 0.1 equiv.). Add the solvent acetonitrile and stir well to dissolve them, and prepare a 2.0 mL mixed solution. Pump the mixed solution into a microfluidic reactor with a total retention volume of 2.0 mL and an inner pipe diameter of 1.0 mm, and carry out a photoreaction at room temperature (the wavelength of light is 390 nm). The residence time of the reaction in the microfluidic reactor is 20 minutes. After the reaction is completed, collect the reaction solution and extract it with ethyl acetate and saturated brine (3 × 25 mL). Combine the organic layers, dry with anhydrous sodium sulfate, distill off the solvent under reduced pressure, and obtain the product 3ae, 33.9 mg, with a separation yield of 82%.

[0088] The characterization data of the product 3ae are as follows: 1 H NMR (400 MHz, Chloroform-d) δ 7.36–7.32 (m, 2H), 7.30–7.27 (m, 3H), 3.27–3.21 (m, 1H), 1.74–1.58 (m, 4H), 1.57–1.40 (m, 8H). 13 C NMR (101 MHz, Chloroform-d) δ 135.0, 129.5, 129.2, 127.8, 53.8, 35.0, 28.5, 27.5. HRMS (ESI) m / z: calcd for C 13 H 19 S [M + H] + : 207.1202, found: 207.1213.

[0089] Example 6:

[0090]

[0091] Weigh S-(p-tolyl) benzenesulfonate (0.2 mmol, 1.0 equiv.), cyclohexane (1.0 mmol, 5.0 equiv.), and (tetrabutylammonium chloride) ferric chloride complex (0.02 mmol, 0.1 equiv.) in sequence. Add the solvent acetonitrile and stir well to dissolve them to prepare a 2.0 mL mixed solution. Pump the mixed solution into a microfluidic reactor with a total retention volume of 2.0 mL and an inner pipe diameter of 1.0 mm, and carry out a photoreaction at room temperature (the wavelength of light is 390 nm). The residence time of the reaction in the microfluidic reactor is 20 minutes. After the reaction is completed, collect the reaction solution and extract it with ethyl acetate and saturated brine (3 × 25 mL). Combine the organic layers, dry them with anhydrous sodium sulfate, distill off the solvent under reduced pressure, and obtain the product 3bb, 35.1 mg, with a separation yield of 85%.

[0092] The characterization data of the product 3bb are as follows: 1 H NMR (400 MHz, Chloroform-d) δ 7.17–7.14 (m, 2H), 7.13–7.10 (m, 2H), 3.33–3.28 (m, 1H), 2.36 (s, 3H), 1.85–1.77 (m, 2H), 1.66–1.59 (m, 4H), 1.54–1.40 (m, 4H). 13 C NMR (101 MHz, Chloroform-d) δ 138.2, 132.8, 132.4, 130.1, 46.9, 33.4, 25.5, 25.0, 21.1. HRMS (ESI) m / z: calcd for C 13 H 19 S [M+H] + : 207.1202, found: 207.1207.

[0093] Example 7:

[0094]

[0095] Weigh S-(4-methoxyphenyl) benzenesulfonate (0.2 mmol, 1.0 equiv.), cyclohexane (1.0 mmol, 5.0 equiv.), and (tetrabutylammonium chloride) ferric chloride complex (0.02 mmol, 0.1 equiv.) in sequence. Add the solvent acetonitrile and stir well to dissolve them to prepare a 2.0 mL mixed solution. Pump the mixed solution into a microfluidic reactor with a total retention volume of 2.0 mL and an inner pipe diameter of 1.0 mm, and carry out a photoreaction at room temperature (the wavelength of light is 390 nm). The residence time of the reaction in the microfluidic reactor is 20 minutes. After the reaction is completed, collect the reaction solution and extract it with ethyl acetate and saturated brine (3 × 25 mL). Combine the organic layers, dry them with anhydrous sodium sulfate, distill off the solvent under reduced pressure, and obtain the product 3cb, 42.3 mg, with a separation yield of 95%.

[0096] The characterization data of the product 3cb are as follows: 1 H NMR (400 MHz, Chloroform-d) δ 7.34–7.30 (m, 2H), 6.83–6.80 (m, 2H), 3.80 (s, 3H), 3.34–3.29 (m, 1H), 1.85–1.76 (m, 2H), 1.67–1.58 (m, 4H), 1.54–1.40 (m, 4H). 13 C NMR (101 MHz, Chloroform-d) δ 158.8, 133.4, 128.4, 115.3, 55.3, 47.0, 33.4, 25.5, 25.0. HRMS (ESI) m / z: calcd for C 13 H 19 OS [M + H] + : 223.1151, found: 223.1164.

[0097] Example 8:

[0098]

[0099] Weigh successively S-(4-tert-butylphenyl) benzenesulfonate (0.2 mmol, 1.0 equiv.), cyclohexane (1.0 mmol, 5.0 equiv.), (tetrabutylammonium chloride) iron(III) chloride complex (0.02 mmol, 0.1 equiv.), add the solvent acetonitrile and stir well to dissolve it, and prepare a 2.0 mL mixed solution. Pump the mixed solution into a microfluidic reactor with a total retention volume of 2.0 mL and an inner pipe diameter of 1.0 mm, and carry out a photoreaction at room temperature (the wavelength of light is 390 nm). The residence time of the reaction in the microfluidic reactor is 20 minutes. After the reaction is completed, collect the reaction solution and extract it with ethyl acetate and saturated brine (3×25 mL). Combine the organic layers, dry with anhydrous sodium sulfate, distill off the solvent under reduced pressure, and obtain the product 3db, 44.2 mg, with a separation yield of 89%.

[0100] The characterization data of the product 3db are as follows: 1 H NMR(400MHz,Chloroform-d)δ7.26(d,J=6.9Hz,2H),7.15(d,J=6.9Hz,2H),3.34–3.28(m,1H),1.85–1.77(m,2H),1.67–1.57(m,4H),1.55–1.39(m,4H),1.34(s,9H). 13 C NMR(101MHz,Chloroform-d)δ149.8,134.3,130.9,127.2,46.9,34.4,33.4,31.2,25.5,25.0.HRMS(ESI)m / z:calcd for C 16 H 25 S[M+H] + :249.1671,found:249.1683.

[0101] Example 9:

[0102]

[0103] Weigh successively S-(3-bromophenyl)benzenesulfonate (0.2 mmol, 1.0 equiv.), cyclohexane (1.0 mmol, 5.0 equiv.), (tetrabutylammonium chloride)iron(III) chloride complex (0.02 mmol, 0.1 equiv.), add the solvent acetonitrile and stir well to dissolve it, and prepare a 2.0 mL mixed solution. Pump the mixed solution into a microfluidic reactor with a total retention volume of 2.0 mL and a pipe inner diameter of 1.0 mm, and carry out a photoreaction at room temperature (the wavelength of light is 390 nm). The reaction residence time in the microfluidic reactor is 20 minutes. After the reaction is completed, collect the reaction solution and extract it with ethyl acetate and saturated brine (3 × 25 mL). Combine the organic layers, dry with anhydrous sodium sulfate, distill off the solvent under reduced pressure, and obtain the product 3eb, 43.4 mg, with a separation yield of 80%.

[0104] The characterization data of the product 3eb are as follows: 1 H NMR (400 MHz, Chloroform-d) δ 7.39–7.34 (m, 1H), 7.27–7.23 (m, 3H), 3.26–3.31 (m, 1H), 1.85–1.76 (m, 2H), 1.68–1.58 (m, 4H), 1.55–1.40 (m, 4H). 13 C NMR (101 MHz, Chloroform-d) δ 136.7, 132.4, 129.7, 129.5, 129.2, 122.32, 47.0, 33.3, 25.5, 25.0. HRMS (ESI) m / z: calcd for C 12 H 16 BrS[M+H] + : 271.0151, found: 271.0170.

[0105] Example 10: Scale-up experiment

[0106]

[0107] Weigh successively S-phenylthiophenyl sulfone (2.0 mmol, 1.0 equiv.), 1,4-dioxane (10.0 mmol, 5.0 equiv.), and (tetrabutylammonium chloride) ferric chloride complex (0.2 mmol, 0.1 equiv.). Add solvent acetonitrile and stir well to dissolve them to prepare a 20.0 mL mixed solution. Pump the mixed solution into a microfluidic reactor with a total retention volume of 2.0 mL and a pipe inner diameter of 1.0 mm, and carry out a photoreaction at room temperature (the wavelength of light is 390 nm). The residence time of the reaction in the microfluidic reactor is 20 minutes. After the reaction is completed, collect the reaction solution and extract it with ethyl acetate and saturated brine (3×25 mL). Combine the organic layers, dry with anhydrous sodium sulfate, distill off the solvent under reduced pressure, and obtain the product 3aa, 320 mg, with a separation yield of 81%.

[0108] Comparative Example 1: Conventional reaction device

[0109]

[0110] Weigh successively S-phenylthiophenyl sulfone (0.2 mmol, 1.0 equiv.), 1,4-dioxane (1.0 mmol, 5.0 equiv.), and (tetrabutylammonium chloride) ferric chloride complex (0.02 mmol, 0.1 equiv.). Add solvent acetonitrile and stir well to dissolve them to prepare a 2.0 mL mixed solution. Carry out a photoreaction on the mixed solution under nitrogen protection at room temperature (the wavelength of light is 390 nm) for 5 hours. After the reaction is completed, collect the reaction solution and extract it with ethyl acetate and saturated brine (3×25 mL). Combine the organic layers, dry with anhydrous sodium sulfate, distill off the solvent under reduced pressure, and obtain the product 3aa, 27.5 mg, with a separation yield of 70%.

[0111] Comparative Example 2: Without adding tetrabutylammonium chloride

[0112]

[0113] Weigh successively S-phenylthiophenyl sulfone (0.2 mmol, 1.0 equiv.), tetrahydrofuran (1.0 mmol, 5.0 equiv.), and iron(III) chloride (0.02 mmol, 0.1 equiv.), add the solvent acetonitrile, stir well to dissolve it, and prepare a 2.0 mL mixed solution. Pump the mixed solution into a microfluidic reactor with a total retention volume of 2.0 mL and an inner pipe diameter of 1.0 mm, and carry out a photoreaction at room temperature (the wavelength of the light is 390 nm). The residence time of the reaction in the microfluidic reactor is 20 minutes. After the reaction is completed, collect the reaction solution, extract it with ethyl acetate and saturated brine (3 × 25 mL), combine the organic layers, dry with anhydrous sodium sulfate, distill off the solvent under reduced pressure, and obtain the product 3ac by silica gel column chromatography (petroleum ether:ethyl acetate = 20:1), with a separation yield of 36%.

[0114] Comparative Example 3: Without adding iron(III) chloride

[0115]

[0116] Weigh successively S-phenylthiophenyl sulfone (0.2 mmol, 1.0 equiv.), 1,4-dioxane (1.0 mmol, 5.0 equiv.), and tetrabutylammonium chloride (0.02 mmol, 0.1 equiv.), add the solvent acetonitrile, stir well to dissolve it, and prepare a 2.0 mL mixed solution. Pump the mixed solution into a microfluidic reactor with a total retention volume of 2.0 mL and an inner pipe diameter of 1.0 mm, and carry out a photoreaction at room temperature (the wavelength of the light is 390 nm). The residence time of the reaction in the microfluidic reactor is 20 minutes. After the reaction is completed, collect the reaction solution, extract it with ethyl acetate and saturated brine (3 × 25 mL), combine the organic layers, dry with anhydrous sodium sulfate, distill off the solvent under reduced pressure, and spot plate (thin layer chromatography) to find that no target product is formed.

[0117] Comparative Example 4:

[0118]

[0119] Weigh successively S-phenylthiophenyl sulfone (0.2 mmol, 1.0 equiv.), 1,4-dioxane (1.0 mmol, 5.0 equiv.), iron(III) chloride (0.02 mmol, 0.1 equiv.), tetrabutylammonium chloride (0.02 mmol, 0.1 equiv.), add the solvent acetonitrile and stir well to dissolve it to prepare a 2.0 mL mixed solution. Pump the mixed solution into a microfluidic reactor with a total retention volume of 2.0 mL and an inner pipe diameter of 1.0 mm, and carry out a photoreaction at room temperature (the wavelength of light is 390 nm). The residence time of the reaction in the microfluidic reactor is 20 minutes. After the reaction is completed, collect the reaction solution and extract it with ethyl acetate and saturated brine (3 × 25 mL). Combine the organic layers, dry with anhydrous sodium sulfate, distill off the solvent under reduced pressure, and obtain the product 3aa, 29.4 mg, with a separation yield of 75% through silica gel column chromatography (petroleum ether:ethyl acetate = 20:1).

[0120] Example 11: Screening of complexation reaction conditions

[0121] FeCl3 + TBACl → TBAFeCl4

[0122] Add iron(III) chloride (162.3 mg, 1.0 mmol), tetrabutylammonium chloride (276.5 mg, 1.0 mmol) and 1.0 mL of solvent to a 20 mL round-bottom flask respectively. Stir the resulting mixture for a certain time under a nitrogen atmosphere at room temperature, then distill it under reduced pressure and recrystallize it with petroleum ether / ethyl acetate to obtain the product (tetrabutylammonium chloride) iron(III) chloride complex (TBAFCl4).

[0123] Among them, the solvents used are acetonitrile, dimethyl sulfoxide, methanol, N,N-dimethylformamide, ethyl acetate, dichloromethane, acetone respectively; the stirring times are 10 min, 20 min, 30 min, 1 h respectively. The yields of the final product (tetrabutylammonium chloride) iron(III) chloride complex are shown in Table 1.

[0124] Table 1 Screening of complexation reaction conditions

[0125] Serial number Solvent Stirring time Yield of complex / % 1 Acetonitrile 30 min 99％ 2 Dimethyl sulfoxide 30 min 65％ 3 Methanol 30 min 75％ 4 N,N-Dimethylformamide 30 min 83％ 5 Ethyl acetate 30 min 35％ 6 Dichloromethane 30 min 88％ 7 Acetone 30 min 79％ 8 Acetonitrile 10 min 51％ 9 Acetonitrile 20 min 76％ 10 Acetonitrile 1h 98％

[0126] Example 12: Screening of photoreaction conditions

[0127]

[0128] The experimental method was the same as that in Example 1, except that the catalytic systems were respectively (tetrabutylammonium chloride) ferric chloride complex, (tetraethylammonium chloride) ferric chloride complex (the synthesis method was the same as that in Example 11), ferric chloride / tetrabutylammonium chloride, ferric chloride / sodium chloride, ferric chloride, iron(III) trifluoromethanesulfonate, iron(III) acetylacetonate, ferrous acetate, ferrous sulfate, ferrocene; the solvents were respectively acetonitrile, dimethyl sulfoxide, methanol, N,N-dimethylformamide, ethyl acetate, dichloromethane, acetone, and the separation yields of the final product 3aa are shown in Table 2.

[0129] Table 2 Screening of reaction conditions

[0130]

[0131]

[0132] In summary, the thioalkylated products represented by Formula 3 provided by the present invention can be used to synthesize and design specific site modifications of natural products and drug molecules and can be applied to multiple fields such as new drug research and development, materials, etc. At the same time, the present invention enhances the mass transfer and heat transfer efficiency of the reaction process based on microfluidic field technology, and the reaction is precisely controllable, which also provides a new idea for the large-scale production of high-value-added sulfur-containing compounds in industry.

[0133] The present invention provides an idea and method for realizing the alkylation of thiosulfonates based on microfluidic field technology. There are many specific methods and ways to implement this technical solution. The above description is only the preferred embodiment of the present invention. It should be noted that for those of ordinary skill in the art, without departing from the principle of the present invention, several improvements and modifications can be made, and these improvements and modifications should also be regarded as the protection scope of the present invention. Each component not clearly defined in this embodiment can be realized by existing technologies.

Claims

1. A method for realizing the alkylation of thiosulfonate based on microfluidic technology, characterized in that, Mix the thiosulfonate compound 1 with compound 2, an iron catalyst, a ligand, and a first solvent to obtain a mixture; pump the mixture into a microfluidic reactor of a microfluidic reaction device for a photoreaction to obtain the thio product 3; Among them, the structure of the thiosulfonate compound 1 is shown in formula 1, the structure of compound 2 is shown in formula 2, and the structure of the thio product 3 is shown in formula 3: Among them, R is selected from substituted or unsubstituted phenyl; R1 and R2 are independently selected from substituted or unsubstituted C1-C6 alkyl; wherein, R1 and R2 can be connected through C or O to form a 3- to 8-membered ring; Among them, the substitution is selected from being substituted by 1 to 5 identical or different substituents; the substituents are C1-C4 alkyl, C1-C4 alkoxy, or halogen.

2. The method according to claim 1, wherein, R is selected from substituted or unsubstituted phenyl; R1 and R2 are independently selected from substituted or unsubstituted C1-C6 alkyl; wherein, R1 and R2 can be connected through C or O to form a 5- to 7-membered ring; Among them, the substituents are C1-C4 alkyl, C1-C2 alkoxy, or halogen; Preferably, R is selected from substituted or unsubstituted phenyl; R1 and R2 are independently selected from substituted or unsubstituted C1-C6 alkyl; wherein, R1 and R2 can be connected through C or O to form a 5- to 7-membered ring; Among them, the substituents are methyl, tert-butyl, methoxy, or bromine.

3. The method according to claim 1, wherein Mix the iron catalyst, the ligand, and a second solvent, stir under an inert gas protection for complexation, remove the solvent, and perform recrystallization to obtain an iron catalyst / ligand complex; mix the thiosulfonate compound 1 with compound 2, the iron catalyst / ligand complex, and a first solvent to obtain a mixture; pump the mixture into a microfluidic reactor of a microfluidic reaction device for a photoreaction to obtain the thio product 3.

4. The method according to claim 3, characterized in that, The iron catalyst is any one or a combination of several of ferric chloride, iron trifluoromethanesulfonate, ferrous chloride, ferrous acetylacetonate, ferric acetylacetonate, ferrous acetate, iron(III) sulfate heptahydrate, ferrocene, ferrous oxalate dihydrate, ferrous sulfate, ferric bromide, and 1,1'-bis(diphenylphosphino)ferrocene; and / or, the ligand is any one or a combination of two of tetrabutylammonium chloride and tetraethylammonium chloride; and / or, the first solvent is any one or a combination of several of acetonitrile, dimethyl sulfoxide, methanol, N,N-dimethylformamide, ethanol, N,N-dimethylacetamide, trifluoroethanol, ethyl acetate, dichloromethane, isopropanol, acetone, 1,2-dichloroethane, p-xylene, hexafluoroisopropanol, toluene, and water; and / or, the second solvent is any one or a combination of several of acetonitrile, dimethyl sulfoxide, methanol, N,N-dimethylformamide, ethanol, N,N-dimethylacetamide, trifluoroethanol, ethyl acetate, dichloromethane, isopropanol, acetone, 1,2-dichloroethane, p-xylene, hexafluoroisopropanol, toluene, and water.

5. The method according to claim 3, characterized in that, The molar ratio of the iron catalyst to the ligand is 1.0:(1.0 - 2.5); and / or, the complexation is carried out at room temperature; and / or, the time of the complexation is 10 min to 2 h; and / or, the inert gas is nitrogen.

6. The method according to claim 3, characterized in that, The molar ratio of the thiosulfonate compound 1 to the compound 2 and the iron catalyst / ligand complex is 1.0:(2.0 - 20.0):(0.05 - 1.0).

7. The method according to claim 1 or 3, characterized in that, In the mixed solution, the concentration of the thiosulfonate compound 1 is 0.01 mmol / mL to 0.20 mmol / mL.

8. The method according to claim 1 or 3, characterized in that, For the photoreaction, the reaction temperature is room temperature; and / or, for the photoreaction, the residence time in the microfluidic reactor is 30 s to 1 h.

9. The method according to claim 1 or 3, characterized in that, For the photoreaction, the wavelength of the light is 360 nm to 600 nm.

10. The method according to claim 1 or 3, characterized in that The microfluidic reaction device includes a connecting pipeline, a feeding pump, a microfluidic reactor, a light source and a receiver; wherein, the feeding pump, the microfluidic reactor and the receiver are connected in series in sequence through the connecting pipeline; the light source is located outside the microfluidic reactor, and its illumination range covers the microfluidic reactor.

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