Method for realizing cross coupling of alkyl thianthrene onium salt and terminal alkyne through concerted catalysis of visible light and copper

Abstract

The invention belongs to the field of organic chemical synthesis, and relates to a method for realizing cross coupling of alkyl thianthrene onium salt and terminal alkyne through synergistic catalysis of visible light and copper. The method comprises the following steps: mixing an alkyl thianthrene onium salt compound 1 with a phenylacetylene compound 2, a ligand, a copper catalyst, alkali and a solvent to obtain a mixed solution; and pumping the mixed solution into a micro-flow field reactor of the micro-flow field reaction device, and carrying out a photoreaction to obtain a terminal alkyne alkylation product 3. According to the invention, the cheap metal catalyst and the green solvent are innovatively adopted, so that the reaction cost is reduced; the reaction process is driven by visible light and carried out in a room temperature environment, and the yield of the product can reach 98%; the method provided by the invention ingeniously avoids the defects of multi-step complexity, time consumption, high catalyst cost, low atomic efficiency and the like in the traditional synthesis method.

Description

Technical Field

[0001] The present invention belongs to the field of organic chemical synthesis and relates to a method for realizing the cross-coupling of alkyl thianthrenium salts and terminal alkynes through the synergistic catalysis of visible light and copper. Background Art

[0002] Alkyl groups are one of the most widely used groups in organic synthesis and play an important role in constructing complex molecules and functionalized compounds. In recent years, sulfonium salts have gradually become important reagents in organic synthesis due to their unique chemical properties and reactivity. Especially, the cleavage reaction of the C(sp 3 )-S bond in sulfonium salts provides a new approach for alkylation reactions. However, the application of traditional sulfonium salts in alkylation reactions is restricted by many factors, such as harsh reaction conditions and limited substrate scope.

[0003] In recent years, significant progress has been made in the research of sulfonium salts. In 2019, the application of aryl sulfonium salts in C-H bond functionalization reactions was disclosed, demonstrating their great potential in arylation reactions (Nature, 2019, 567, 223-228). Subsequently, in 2021, a method for electrochemically synthesizing 1,2-disubstituted sulfonium salts was disclosed and successfully applied to the synthesis of aziridines (Nature, 2021, 596, 74-79). These studies have opened up new directions for the application of sulfonium salts in organic synthesis.

[0004] However, traditional sulfonium salts still face some challenges in alkylation reactions. For example, the reaction usually requires strong oxidants or high-temperature conditions, and has poor functional group compatibility with substrates, especially low tolerance to sensitive groups such as halogens (such as -Cl, -Br, -I). In addition, traditional sulfonium salts often accompany side reactions during the reaction, resulting in low reaction selectivity.

[0005] In recent years, photocatalytic reactions have gradually become a popular research field in organic synthesis due to their mild reaction conditions and efficient electron transfer processes. Photocatalytic reactions use visible light to excite catalysts to generate highly active radical intermediates, thereby realizing the construction of C(sp 3 )-C bonds. Compared with traditional thermal catalytic reactions, photocatalytic reactions do not require strong oxidants or reductants, have milder reaction conditions, can effectively avoid the occurrence of side reactions, and have higher selectivity and are environmentally friendly.

[0006] Based on this, developing a photocatalytic sulfonium salt alkylation reaction has important research significance. Through visible light catalysis, the construction of C(sp 3)-S bond selectively breaks to generate alkyl radicals, which then undergo coupling reactions with various nucleophiles. This method can not only overcome the limitations of traditional sulfonium salt reactions but also provide an efficient and green new strategy for the synthesis of complex molecules. Summary of the Invention

[0007] The technical problem to be solved by the present invention is to provide a method for the cross-coupling of alkyl thianthrenium salts and terminal alkynes through the synergistic catalysis of visible light and copper in view of the deficiencies of the prior art, so as to solve the problems of cumbersome reaction process, low reaction yield, low atom utilization rate, and difficulty in large-scale synthesis existing in the prior art.

[0008] To solve the above technical problems, the technical solution adopted by the present invention is as follows:

[0009] The present invention discloses a method for the cross-coupling of alkyl thianthrenium salts and terminal alkynes through the synergistic catalysis of visible light and copper. A mixture is obtained by mixing an alkyl thianthrenium salt compound 1, a phenylacetylene compound 2, a ligand, a copper catalyst, a base, and a solvent; the mixture is pumped into a microfluidic reactor of a microfluidic reaction device for a photoreaction to obtain a terminal alkyne alkylation product 3;

[0010] Among them, the structure of the alkyl thianthrenium salt compound 1 is shown in Formula 1, the structure of the phenylacetylene compound 2 is shown in Formula 2, and the structure of the terminal alkyne alkylation product 3 is shown in Formula 3:

[0011]

[0012] n is an integer between 1 and 6;

[0013] m is an integer between 0 and 5;

[0014] R1 is selected from halogen, substituted or unsubstituted phenyl, substituted or unsubstituted benzyloxy, substituted or unsubstituted thiophenyl, substituted or unsubstituted C1-C4 alkoxy, or substituted or unsubstituted adamantyl;

[0015] R2 is selected from halogen, substituted or unsubstituted C1-C4 alkoxy, methoxycarbonyl, trifluoromethyl, or ethoxycarbonyl;

[0016] Among them, the substitution is selected from being substituted by 1 to 3 identical or different substituents; the substituent is halogen.

[0017] In some embodiments, preferably,

[0018] n is an integer between 1 and 4;

[0019] m is an integer between 1 and 2;

[0020] R1 is selected from fluorine, chlorine, bromine, substituted or unsubstituted phenyl, benzyloxy, thiophenyl, C1-C2 alkoxy or adamantyl;

[0021] R2 is selected from fluorine, chlorine, bromine, C1-C2 alkoxy or methoxycarbonyl;

[0022] Wherein, the substitution is selected from being substituted by 1 to 3 identical or different substituents; the substituents are fluorine, chlorine or bromine.

[0023] In some embodiments, further preferably,

[0024] n is an integer between 1 and 4;

[0025] m is an integer between 1 and 2;

[0026] R1 is selected from chlorine, substituted or unsubstituted phenyl, benzyloxy, thiophenyl, methoxy or adamantyl;

[0027] R2 is selected from chlorine, methoxy or methoxycarbonyl;

[0028] Wherein, the substitution is selected from being substituted by 1 to 3 identical or different substituents; the substituents are fluorine or bromine.

[0029] In some embodiments, the ligand is 4,7-diphenyl-1,10-phenanthroline; and / or, the copper catalyst is copper thiophene-2-carboxylate; and / or, the base is any one or a combination of several of triethylamine, potassium carbonate, sodium carbonate, sodium bicarbonate, tetramethylethylenediamine, 4-dimethylaminopyridine and 2,6-dimethylpyridine; and / or, the solvent is any one or a combination of two of acetonitrile and methanol.

[0030] In some embodiments, preferably, the base is potassium carbonate.

[0031] In some embodiments, preferably, the ligand is 4,7-diphenyl-1,10-phenanthroline; and / or, the copper catalyst is copper thiophene-2-carboxylate; and / or, the solvent is a mixture of acetonitrile and methanol in a volume ratio of (1.0 to 2.0):(1.0 to 2.0).

[0032] In some embodiments, further preferably, the ligand is 4,7-diphenyl-1,10-phenanthroline; and / or, the copper catalyst is copper thiophene-2-carboxylate; and / or, the solvent is a mixture of acetonitrile and methanol in a volume ratio of 1.0:1.0.

[0033] In some embodiments, the molar ratio of the alkylthianthrenium salt compound 1 to the phenylacetylene compound 2 is (1.0 - 2.0):(1.0 - 2.0); and / or, the molar ratio of the alkylthianthrenium salt compound 1 to the ligand is (5.0 - 10.0):1.0; and / or, the molar ratio of the alkylthianthrenium salt compound 1 to the copper catalyst is (5.0 - 15.0):1.0; and / or, the molar ratio of the alkylthianthrenium salt compound 1 to the base is 1.0:(1.0 - 5.0).

[0034] In some embodiments, preferably, the molar ratio of the alkylthianthrenium salt compound 1 to the phenylacetylene compound 2 is 1.0:1.2; and / or, the molar ratio of the alkylthianthrenium salt compound 1 to the ligand is 8.3:1.0; and / or, the molar ratio of the alkylthianthrenium salt compound 1 to the copper catalyst is 10.0:1.0; and / or, the molar ratio of the alkylthianthrenium salt compound 1 to the base is 1.0:3.0.

[0035] In some embodiments, in the mixed solution, the concentration of the alkylthianthrenium salt compound 1 is 0.01 mmol / mL - 0.50 mmol / mL.

[0036] In some embodiments, preferably, in the mixed solution, the concentration of the alkylthianthrenium salt compound 1 is 0.05 mmol / mL - 0.25 mmol / mL.

[0037] In some embodiments, more preferably, in the mixed solution, the concentration of the alkylthianthrenium salt compound 1 is 0.05 mmol / mL - 0.10 mmol / mL.

[0038] In some embodiments, for the photoreaction, the reaction temperature is room temperature; and / or, the residence time of the photoreaction in the microfluidic reactor is 10 min - 60 min.

[0039] In some embodiments, preferably, for the photoreaction, the reaction temperature is room temperature; and / or, the residence time of the photoreaction in the microfluidic reactor is 10 min - 30 min.

[0040] In some embodiments, more preferably, for the photoreaction, the reaction temperature is room temperature; and / or, the residence time of the photoreaction in the microfluidic reactor is 20 min.

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

[0042] In some embodiments, preferably, in the photoreaction, the wavelength of the light is 360 nm - 470 nm.

[0043] In some embodiments, further preferably, in the photoreaction, the wavelength of the light is 450 nm to 455 nm.

[0044] In some embodiments, the microfluidic reaction device includes a connecting pipe, a feed pump, a microfluidic reactor, a light source, and a receiver; wherein, the feed pump, the microfluidic reactor, and the receiver are connected in series through pipes in sequence.

[0045] In some embodiments, the light source is located outside the microfluidic reactor, and its illumination range covers the microfluidic reactor.

[0046] Wherein, the material of the microfluidic reactor is perfluoroalkoxy resin.

[0047] Wherein, the microfluidic reactor is a tubular reactor, with an inner diameter of 0.5 mm to 10.0 mm, preferably 0.5 mm to 2.0 mm, and further preferably 1.0 mm.

[0048] Wherein, when the material of the microfluidic reactor is perfluoroalkoxy resin, the material is a transparent material, the light source is located outside the microfluidic reactor, and its illumination range covers the microfluidic reactor.

[0049] Wherein, the light source is from an LED lamp, and the power of the LED lamp is 10 W to 36 W, preferably 10 W to 24 W, and further preferably 12 W.

[0050] Wherein, the terminal alkyne alkylation product 3 prepared by the present invention can be applied to the specific site modification of terminal alkynides in synthetic design.

[0051] Advantageous effects:

[0052] (1) The molecular structure of the alkyl thianthrenium salt compounds used in the present invention has both the characteristics of simplicity and high stability. It not only has low volatility and weak corrosiveness, but also shows excellent industrial application potential. Such reagents can be prepared from commercially available raw materials through a simple synthesis route, realizing the simplification of the process flow. Compared with the defects of traditional processes such as long multi-step reactions, strong dependence on precious metal catalysts, and poor atom economy, the present invention effectively improves the overall efficiency of the reaction system through molecular design innovation, providing a new path for green chemical synthesis.

[0053] (2) The present invention does not need to use expensive transition metal catalysts, but uses cheap and easily available copper catalysts, reducing the reaction cost.

[0054] (3) The yield of the terminal alkyne alkylation product prepared by the present invention can reach 56 - 98%.

[0055] (4) The present invention innovatively adopts inexpensive metal catalysts and green solvents, reducing the reaction cost; the reaction process is driven by visible light and carried out at room temperature, and the yield of the product can reach 98%; the method provided by the present invention ingeniously avoids the disadvantages of multi-step complexity, time-consuming, high catalyst cost and low atomic efficiency in traditional synthesis methods. BRIEF DESCRIPTION OF THE DRAWINGS

[0056] The present invention will be further specifically described below 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 physical diagram of the microfluidic reaction device used in the embodiment of the present invention.

[0058] Figure 2 It is the 1H NMR spectrum of product 3aa.

[0059] Figure 3 It is the 13C NMR spectrum of product 3aa.

[0060] Figure 4 It is the 1H NMR spectrum of product 3ab.

[0061] Figure 5 It is the 13C NMR spectrum of product 3ab.

[0062] Figure 6 It is the 19F NMR spectrum of product 3ab.

[0063] Figure 7 It is the 1H NMR spectrum of product 3ac.

[0064] Figure 8 It is the 13C NMR spectrum of product 3ac.

[0065] Figure 9 It is the 1H NMR spectrum of product 3ad.

[0066] Figure 10 It is the 13C NMR spectrum of product 3ad.

[0067] Figure 11 It is the 1H NMR spectrum of product 3ae.

[0068] Figure 12 It is the 13C NMR spectrum of product 3ae.

[0069] Figure 13 It is the 1H NMR spectrum of product 3af.

[0070] Figure 14 It is the 13C NMR spectrum of product 3af.

[0071] Figure 15 It is the 1H NMR spectrum of product 3ag.

[0072] Figure 16 It is the carbon NMR spectrum of product 3ag.

[0073] Figure 17 It is the hydrogen NMR spectrum of product 3ah.

[0074] Figure 18 It is the carbon NMR spectrum of product 3ah.

[0075] Figure 19 It is the hydrogen NMR spectrum of product 3ba.

[0076] Figure 20 It is the carbon NMR spectrum of product 3ba.

[0077] Figure 21 It is the hydrogen NMR spectrum of product 3ca.

[0078] Figure 22 It is the carbon NMR spectrum of product 3ca. Detailed implementation manners

[0079] 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.

[0080] In the following embodiments, unless otherwise specified, the experimental methods are all conventional methods; unless otherwise specified, the reagents and materials can be obtained from commercial channels.

[0081] The alkyl thianthrenium salt compound 1 used in the embodiments of the present invention can be commercially purchased or prepared according to the prior art (Angew. Chem. Int. Ed. 2021, 60, 21756–21760).

[0082] The physical diagram of the microfluidic reaction device used in the embodiments of the present invention is as Figure 1 shown ( Figure 1 Figure A in Figure 1 is the physical diagram of the microfluidic reaction device when no reaction occurs, and

[0083] Figure B in

[0084] is the physical diagram of the microfluidic reaction device during the reaction process), and 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 sequentially connected in series through pipelines.

[0083] Among them, the feeding pump has the model of Baoding Leifu Fluid Technology Co., Ltd, TYD01-01-CE type.

[0084] Among them, the light source is located outside the microfluidic reactor, and its illumination range covers the microfluidic reactor.

[0085] Among them, the material of the microfluidic reactor is perfluoroalkoxy resin.

[0086] Among them, the microfluidic reactor is a tubular reactor with an inner diameter of 1.0 mm.

[0087] Among them, when the material of the microfluidic reactor is perfluoroalkoxy resin, the material is a transparent material, the light source is located outside the microfluidic reactor, and its illumination range covers the microfluidic reactor.

[0088] Among them, the light source comes from an LED lamp, and the power of the LED lamp is 12 W.

[0089] Example 1:

[0090]

[0091] Weigh 5-(3-phenylpropyl)-5H-dithioxanthene 5-ium trifluoromethanesulfonate (0.20 mmol, 1.0 equiv.), p-methoxyphenylacetylene (0.24 mmol, 1.2 equiv.), 4,7-diphenyl-1,10-phenanthroline (0.024 mmol, 0.12 equiv.), copper(II) thiophene-2-carboxylate (0.02 mmol, 0.10 equiv.), potassium carbonate (0.60 mmol, 3.0 equiv.) in sequence. Dissolve the above substances in 1.0 mL of acetonitrile and 1.0 mL of methanol solution, and stir well to dissolve them to obtain a mixed solution. Transfer the mixed solution to a syringe, and use a syringe pump to pump it into the microfluidic reactor (volume: 2.0 mL) of the microfluidic reaction device at a flow rate of 0.1 mL / min for a photoreaction (blue light of 450 nm - 455 nm) at room temperature. The residence time of the photoreaction in the microfluidic reactor is 20 min. Collect the effluent and monitor it by TLC. Quench the reaction after the reaction is completed, then extract the reaction solution with dichloromethane and saturated brine (3 × 25 mL), combine the organic layers, dry with anhydrous sodium sulfate, remove the solvent by rotary evaporation, and obtain the product 3aa, 47 mg, with a separation yield of 94% through silica gel column chromatography (petroleum ether: ethyl acetate).

[0092] The characterization data of the product 3aa are as follows: 1 H NMR(400MHz,Chloroform-d)δ7.37–7.32(m,2H),7.31–7.26(m,2H),7.25–7.18(m,3H),6.85–6.79(m,2H),3.79(s,3H),2.81–2.75(m,2H),2.40(t,J=8.0Hz,2H),1.91(m,2H).13 C NMR (101 MHz, Chloroform-d) δ 159.1, 141.8, 132.9, 128.6, 128.4, 125.9, 116.1, 113.9, 88.2, 80.9, 55.3, 34.9, 30.5, 18.9. HRMS (ESI) m / z: calcd for C 18 H 18 ONa [M+Na] + : 273.1250, found: 273.1248. The 1H NMR spectrum of product 3aa is shown in Figure 2 , and the 13C NMR spectrum is shown in Figure 3 .

[0093] Example 2:

[0094]

[0095] Weigh successively 5-(4-fluorophenethyl)-5H-dithioxanthene 5-ium trifluoromethanesulfonate (0.20 mmol, 1.0 equiv.), p-methoxyphenylacetylene (0.24 mmol, 1.2 equiv.), 4,7-diphenyl-1,10-phenanthroline (0.024 mmol, 0.12 equiv.), copper(II) thiophene-2-carboxylate (0.02 mmol, 0.10 equiv.), potassium carbonate (0.60 mmol, 3.0 equiv.). Dissolve the above substances in 1.0 mL of acetonitrile and 1.0 mL of methanol solution, and stir well to dissolve to obtain a mixed solution. Transfer the mixed solution to a syringe, and use an infusion pump to pump it into the microfluidic reactor (with a volume of 2.0 mL) of the microfluidic reaction device at a flow rate of 0.1 mL / min for a photoreaction (blue light of 450 nm - 455 nm) at room temperature. The residence time of the photoreaction in the microfluidic reactor is 20 min. Collect the effluent and monitor it by TLC. Quench the reaction after the reaction is completed, and then extract the reaction solution with dichloromethane and saturated brine (3 × 25 mL). Combine the organic layers, dry over anhydrous sodium sulfate, remove the solvent by rotary evaporation, and obtain product 3ab, 44.24 mg, with a separation yield of 87% by silica gel column chromatography (petroleum ether: ethyl acetate).

[0096] The characterization data of product 3ab are as follows: 1 H NMR (400 MHz, Chloroform-d) δ 7.32–7.27 (m, 2H), 7.26–7.20 (m, 2H), 7.03–6.96 (m, 2H), 6.85–6.78 (m, 2H), 3.79 (s, 3H), 2.87 (t, J = 8.0 Hz, 2H), 2.65 (t, J = 8.0 Hz, 2H). 1313C NMR (101 MHz, Chloroform-d) δ 162.8, 160.4, 159.1, 136.5, 136.4, 132.9, 130.1, 130.0, 115.8, 115.2, 115.0, 113.9, 87.6, 81.3, 55.3, 34.4, 21.9. 19 19F NMR (376 MHz, Chloroform-d) δ -117.10. HRMS (ESI) m / z: calcd for C 17 H 15 FONa [M+Na]+: 277.0999, found: 277.0986. The 1H NMR spectrum of product 3ab is shown in Figure 4 , and the 13C NMR spectrum is shown in Figure 5 , and the 19F NMR spectrum is shown in Figure 6 .

[0097] Example 3:

[0098]

[0099] Weigh successively 5-(4-chlorobutyl)-5H-dithioxanthene 5-ium trifluoromethanesulfonate (0.20 mmol, 1.0 equiv.), p-methoxyphenylacetylene (0.24 mmol, 1.2 equiv.), 4,7-diphenyl-1,10-phenanthroline (0.024 mmol, 0.12 equiv.), copper(II) 2-thiophenecarboxylate (0.02 mmol, 0.10 equiv.), potassium carbonate (0.6 mmol, 3.0 equiv.). Dissolve the above substances in 1.0 mL of acetonitrile and 1.0 mL of methanol solution, and stir well to dissolve to obtain a mixed solution. Transfer the mixed solution to a syringe, and use an infusion pump to pump it into the microfluidic reactor (with a volume of 2.0 mL) of the microfluidic reaction device at a flow rate of 0.1 mL / min for a photoreaction (blue light at 450 nm - 455 nm) at room temperature. The residence time of the photoreaction in the microfluidic reactor is 20 min. Collect the effluent and monitor it by TLC. Quench the reaction after the reaction is completed, and then extract the reaction solution with dichloromethane and saturated brine (3 × 25 mL). Combine the organic layers, dry over anhydrous sodium sulfate, remove the solvent by rotary evaporation, and obtain product 3ac, 38.7 mg, with a separation yield of 87% by silica gel column chromatography (petroleum ether: ethyl acetate).

[0100] The characterization data of product 3ac are as follows: 11H NMR (400 MHz, Chloroform-d) δ 7.37–7.28 (m, 2H), 6.85–6.77 (m, 2H), 3.80 (s, 3H), 3.60 (t, J = 6.0 Hz, 2H), 2.44 (t, J = 4.0 Hz, 2H), 2.01–1.91 (m, 2H), 1.75 (m, 2H). 13 13C NMR (101 MHz, Chloroform-d) δ 159.1, 132.9, 115.9, 113.9, 87.7, 80.9, 55.3, 44.7, 31.7, 26.0, 18.7. HRMS (ESI) m / z: calcd for C 13 H 15 ClONa [M+Na] + : 245.0704, found: 245.0705. The 1H NMR spectrum of product 3ac is shown in Figure 7 , and the 13C NMR spectrum is shown in Figure 8 .

[0101] Example 4:

[0102]

[0103] Weigh successively 5-(3-(benzyloxy)propyl)-5H-dithioxanthene 5-ium trifluoromethanesulfonate (0.20 mmol, 1.0 equiv.), p-methoxyphenylacetylene (0.24 mmol, 1.2 equiv.), 4,7-diphenyl-1,10-phenanthroline (0.024 mmol, 0.12 equiv.), copper(II) 2-thiophenecarboxylate (0.02 mmol, 0.10 equiv.), potassium carbonate (0.60 mmol, 3.0 equiv.). Dissolve the above substances in 1.0 mL of acetonitrile and 1.0 mL of methanol solution, and stir well to dissolve to obtain a mixed solution. Transfer the mixed solution to a syringe, and use an infusion pump to pump it into the microfluidic reactor (with a volume of 2.0 mL) of the microfluidic reaction device at a flow rate of 0.1 mL / min for a photoreaction (blue light at 450 nm - 455 nm) at room temperature. The residence time of the photoreaction in the microfluidic reactor is 20 min. Collect the effluent and monitor it by TLC. Quench the reaction after the reaction is completed, and then extract the reaction solution with dichloromethane and saturated brine (3 × 25 mL). Combine the organic layers, dry over anhydrous sodium sulfate, remove the solvent by rotary evaporation, and obtain product 3ad, 53.27 mg, with a separation yield of 95% by silica gel column chromatography (petroleum ether: ethyl acetate).

[0104] The characterization data of product 3ad are as follows: 11H NMR (400 MHz, Chloroform-d) δ 7.35 (d, J = 4.0 Hz, 2H), 7.34–7.23 (m, 5H), 6.82–6.78 (m, 2H), 4.54 (s, 2H), 3.79 (s, 3H), 3.63 (t, J = 8.0 Hz, 2H), 2.52 (t, J = 7.0 Hz, 2H), 1.91 (m, 2H). 13 13C NMR (101 MHz, Chloroform-d) δ 159.1, 138.6, 132.9, 128.4, 127.7, 127.6, 113.8, 88.0, 80.6, 73.0, 69.0, 55.3, 29.0, 16.3. HRMS (ESI) m / z: calcd for C 19 H 20 O2Na [M+Na] + : 303.1356, found: 303.1357. The 1H NMR spectrum of product 3ad is shown in Figure 9 , and the 13C NMR spectrum is shown in Figure 10 .

[0105] Example 5:

[0106]

[0107] Weigh successively 5-(2-(thiophen-2-yl)ethyl)-5H-dithioxanthene 5-ium trifluoromethanesulfonate (0.20 mmol, 1.0 equiv.), 4-methoxyphenylacetylene (0.24 mmol, 1.2 equiv.), 4,7-diphenyl-1,10-phenanthroline (0.024 mmol, 0.12 equiv.), copper(II) 2-thiophenecarboxylate (0.02 mmol, 0.10 equiv.), potassium carbonate (0.60 mmol, 3.0 equiv.). Dissolve the above substances in 1.0 mL of acetonitrile and 1.0 mL of methanol solution, and stir well to dissolve to obtain a mixed solution. Transfer the mixed solution to a syringe, and use an infusion pump to pump it into the microfluidic reactor (with a volume of 2.0 mL) of the microfluidic reaction device at a flow rate of 0.1 mL / min for a photoreaction (blue light at 450 nm - 455 nm) at room temperature. The residence time of the photoreaction in the microfluidic reactor is 20 min. Collect the effluent and monitor it by TLC. Quench the reaction after the reaction is completed, and then extract the reaction solution with dichloromethane and saturated brine (3 × 25 mL). Combine the organic layers, dry over anhydrous sodium sulfate, remove the solvent by rotary evaporation, and obtain product 3ae, 41.4 mg, with a separation yield of 85% by silica gel column chromatography (petroleum ether: ethyl acetate).

[0108] The characterization data of product 3ae are as follows: 11H NMR (400 MHz, Chloroform-d) δ 7.38–7.29 (m, 2H), 7.15 (t, 1H), 6.97–6.89 (m, 2H), 6.85–6.78 (m, 2H), 3.79 (s, 3H), 3.13 (t, J = 8.0 Hz, 2H), 2.73 (t, J = 8.0 Hz, 2H). 13 13C NMR (101 MHz, Chloroform-d) δ 159.2, 143.3, 132.9, 126.7, 124.8, 123.6, 115.9, 113.9, 87.4, 81.5, 55.3, 29.6, 22.2. HRMS (ESI) m / z: calcd for C 15 H 14 OSNa [M+Na] + : 265.0658 found: 265.0659. The 1H NMR spectrum of product 3ae is shown in Figure 11 , and the 13C NMR spectrum is shown in Figure 12 .

[0109] Example 6:

[0110]

[0111] Weigh successively 5-(3-methoxypropyl)-5H-dithioxanthene 5-ium trifluoromethanesulfonate (0.20 mmol, 1.0 equiv.), p-methoxyphenylacetylene (0.24 mmol, 1.2 equiv.), 4,7-diphenyl-1,10-phenanthroline (0.024 mmol, 0.12 equiv.), copper(II) thiophene-2-carboxylate (0.02 mmol, 0.10 equiv.), potassium carbonate (0.60 mmol, 3.0 equiv.). Dissolve the above substances in 1.0 mL of acetonitrile and 1.0 mL of methanol solution, and stir well to dissolve to obtain a mixed solution. Transfer the mixed solution to a syringe, and use an infusion pump to pump it into the microfluidic reactor (volume 2.0 mL) of the microfluidic reaction device at a flow rate of 0.1 mL / min for a photoreaction (blue light at 450 nm - 455 nm) at room temperature. The residence time of the photoreaction in the microfluidic reactor is 20 min. Collect the effluent and monitor it by TLC. Quench the reaction after the reaction is completed, and then extract the reaction solution with dichloromethane and saturated brine (3 × 25 mL). Combine the organic layers, dry over anhydrous sodium sulfate, remove the solvent by rotary evaporation, and obtain product 3af, 28.19 mg, with a separation yield of 69% by silica gel column chromatography (petroleum ether: ethyl acetate).

[0112] The characterization data of product 3af are as follows: 11H NMR (400 MHz, Chloroform-d) δ 7.35–7.30 (m, 2H), 6.84–6.78 (m, 2H), 3.79 (s, 3H), 3.52 (t, J = 6.0 Hz, 2H), 3.36 (s, 3H), 2.48 (t, J = 8.0 Hz, 2H), 1.85 (m, 2H). 13 13C NMR (101 MHz, Chloroform-d) δ 159.1, 132.9, 116.1, 113.8, 87.9, 80.5, 71.3, 58.7, 55.3, 28.9, 16.2. HRMS (ESI) m / z: calcd for C 13 H 16 O2Na [M+Na] + : 227.1043, found: 227.1042. The 1H NMR spectrum of product 3af is shown in Figure 13 , and the 13C NMR spectrum is shown in Figure 14 .

[0113] Example 7:

[0114]

[0115] Weigh successively 5-(3-(2-bromophenyl)propyl)-5H-dithioxanthene 5-ium trifluoromethanesulfonate (0.20 mmol, 1.0 equiv.), p-methoxyphenylacetylene (0.24 mmol, 1.2 equiv.), 4,7-diphenyl-1,10-phenanthroline (0.024 mmol, 0.12 equiv.), copper(II) 2-thiophenecarboxylate (0.02 mmol, 0.10 equiv.), potassium carbonate (0.60 mmol, 3.0 equiv.). Dissolve the above substances in 1.0 mL of acetonitrile and 1.0 mL of methanol solution, and stir well to dissolve them to obtain a mixed solution. Transfer the mixed solution to a syringe, and use an infusion pump to pump it into the microfluidic reactor (volume 2.0 mL) of the microfluidic reaction device at a flow rate of 0.1 mL / min for a photoreaction (blue light at 450 nm - 455 nm) at room temperature. The residence time of the photoreaction in the microfluidic reactor is 20 min. Collect the effluent and monitor it by TLC. Quench the reaction after the reaction is completed, and then extract the reaction solution with dichloromethane and saturated brine (3 × 25 mL), dry it over anhydrous sodium sulfate, remove the solvent by rotary evaporation, and obtain product 3ag, 57.94 mg, with a separation yield of 88% by silica gel column chromatography (petroleum ether: ethyl acetate).

[0116] The characterization data of product 3ag are as follows: 11H NMR (400 MHz, Chloroform-d) δ 7.53 (m, 1H), 7.38–7.33 (m, 2H), 7.29–7.22 (m, 2H), 7.05 (m, 1H), 6.84–6.79 (m, 2H), 3.79 (s, 3H), 2.94–2.88 (m, 2H), 2.44 (t, J = 8.0 Hz, 2H), 1.92 (m, 2H). 13 13C NMR (101 MHz, Chloroform-d) δ 159.1, 141.0, 132.9, 132.9, 130.6, 127.7, 127.4, 124.5, 116.1, 113.9, 88.0, 81.0, 55.3, 35.3, 28.9, 19.0. HRMS (ESI) m / z: calcd for C 18 H 17 BrONa [M+Na]+: 351.0355, found: 351.0356. The 1H NMR spectrum of product 3ag is shown in Figure 15 , and the 13C NMR spectrum is shown in Figure 16 .

[0117] Example 8:

[0118]

[0119] Weigh successively 5-(((3r,5r,7r)-adamantan-1-yl)methyl)-5H-dithioxanthene-5-ium trifluoromethanesulfonate (1.0 mmol, 1.0 equiv.), 4-methoxyphenylacetylene (0.24 mmol, 1.2 equiv.), 4,7-diphenyl-1,10-phenanthroline (0.024 mmol, 0.12 equiv.), copper(II) thiophene-2-carboxylate (0.02 mmol, 0.10 equiv.), potassium carbonate (0.60 mmol, 3.0 equiv.). Dissolve the above substances in 1.0 mL of acetonitrile and 1.0 mL of methanol solution, and stir well to dissolve to obtain a mixed solution; transfer the mixed solution to a syringe, and use an infusion pump to pump it into a microfluidic reactor (with a volume of 2.0 mL) of a microfluidic reaction device at a flow rate of 0.1 mL / min for a photoreaction (blue light of 450 nm - 455 nm) at room temperature. The residence time of the photoreaction in the microfluidic reactor is 20 min. Collect the effluent and monitor it by TLC. Quench the reaction after the reaction is completed, and then extract the reaction solution with dichloromethane and saturated brine (3 × 25 mL). Combine the organic layers, dry over anhydrous sodium sulfate, remove the solvent by rotary evaporation, and obtain product 3ah, 40.9 mg, with a separation yield of 73% by silica gel column chromatography (petroleum ether: ethyl acetate).

[0120] The characterization data of product 3ah are as follows: 1 H NMR (400 MHz, Chloroform-d) δ 7.29–7.24 (m, 2H), 6.76–6.71 (m, 2H), 3.71 (s, 3H), 2.06 (m, 2H), 1.94–1.88 (m, 3H), 1.70–1.56 (m, 6H), 1.56 - 1.54 (m, 6H). 13 C NMR (101 MHz, Chloroform-d) δ 159.0, 132.9, 116.5, 113.8, 86.1, 82.3, 55.3, 42.1, 37.0, 34.7, 33.1, 28.7. HRMS (ESI) m / z: calcd for C 20 H 24 ONa [M+Na]+: 303.1719, found: 303.1720. The 1H NMR spectrum of product 3ah is shown in Figure 17 , and the 13C NMR spectrum is shown in Figure 18 .

[0121] Example 9:

[0122]

[0123] Weigh successively 5-(3-phenylpropyl)-5H-dithioxanthene 5-ium trifluoromethanesulfonate (0.20 mmol, 1.0 equiv.), 1-chloro-2-ethynylbenzene (0.24 mmol, 1.2 equiv.), 4,7-diphenyl-1,10-phenanthroline (0.024 mmol, 0.12 equiv.), copper(II) 2-thiophenecarboxylate (0.02 mmol, 0.10 equiv.), potassium carbonate (0.60 mmol, 3.0 equiv.). Dissolve the above substances in 1.0 mL of acetonitrile and 1.0 mL of methanol solution, and stir well to dissolve to obtain a mixed solution. Transfer the mixed solution to a syringe, and use an infusion pump to pump it into a microfluidic reactor (with a volume of 2.0 mL) of a microfluidic reaction device at a flow rate of 0.1 mL / min for a photoreaction (blue light of 450 nm - 455 nm) at room temperature. The residence time of the photoreaction in the microfluidic reactor is 20 min. Collect the effluent and monitor it by TLC. Quench the reaction after the reaction is completed, and then extract the reaction solution with dichloromethane and saturated brine (3 × 25 mL). Combine the organic layers, dry with anhydrous sodium sulfate, remove the solvent by rotary evaporation, and obtain product 3ba, 39.7 mg, with a yield of 78% by silica gel column chromatography (petroleum ether: ethyl acetate).

[0124] The characterization data of product 3ba are as follows: 11H NMR (400 MHz, Chloroform-d) δ 7.47–7.42 (m, 1H), 7.41–7.36 (m, 1H), 7.31 (d, J = 4.0 Hz, 1H), 7.28 (d, J = 4.0 Hz, 1H), 7.26–7.23 (m, 2H), 7.22–7.15 (m, 3H), 2.87–2.81 (m, 2H), 2.48 (t, J = 8.0 Hz, 2H), 2.00–1.90 (m, 2H). 13 13C NMR (101 MHz, Chloroform-d) δ 141.7, 135.8, 133.3, 129.2, 128.7, 128.6, 128.4, 126.4, 125.9, 123.8, 95.6, 78.2, 34.7, 30.3, 19.0. HRMS (ESI) m / z: calcd for C 17 H 15 ClNa [M+Na]+: 277.0754, found: 277.0753. The 1H NMR spectrum of product 3ba is shown in Figure 19 , and the 13C NMR spectrum is shown in Figure 20 .

[0125] Example 10:

[0126]

[0127] Weigh successively 5-(3-phenylpropyl)-5H-dithioxanthene 5-ium trifluoromethanesulfonate (0.20 mmol, 1.0 equiv.), methyl 4-ethynylbenzoate (0.24 mmol, 1.2 equiv.), 4,7-diphenyl-1,10-phenanthroline (0.024 mmol, 0.12 equiv.), copper(II) 2-thiophenecarboxylate (0.02 mmol, 0.10 equiv.), potassium carbonate (0.60 mmol, 3.0 equiv.). Dissolve the above substances in 1.0 mL of acetonitrile and 1.0 mL of methanol solution, and stir well to dissolve to obtain a mixed solution. Transfer the mixed solution to a syringe, and use an infusion pump to pump it into the microfluidic reactor (with a volume of 2.0 mL) of the microfluidic reaction device at a flow rate of 0.1 mL / min for a photoreaction (blue light at 450 nm - 455 nm) at room temperature. The residence time of the photoreaction in the microfluidic reactor is 20 min. Collect the effluent and monitor it by TLC. Quench the reaction after the reaction is completed, and then extract the reaction solution with dichloromethane and saturated brine (3 × 25 mL). Combine the organic layers, dry over anhydrous sodium sulfate, remove the solvent by rotary evaporation, and obtain product 3ca, 35 mg, with a separation yield of 63% by silica gel column chromatography (petroleum ether: ethyl acetate).

[0128] The characterization data of product 3ca are as follows: 1 H NMR (400 MHz, Chloroform-d) δ 7.98–7.94 (m, 2H), 7.48–7.43 (m, 2H), 7.33–7.21 (m, 5H), 3.91 (s, 3H), 2.79 (t, J = 8.0 Hz, 2H), 2.44 (t, J = 6.0 Hz, 2H), 1.94 (t, 2H). 13 C NMR (101 MHz, Chloroform-d) δ 166.7, 141.5, 131.5, 129.5, 128.9, 128.8, 128.6, 128.4, 126.0, 93.4, 80.7, 52.2, 34.9, 30.1, 18.9. HRMS (ESI) m / z: calcd for C 19 H 18 O2Na [M+Na]+: 301.1199, found: 301.1199. The 1H NMR spectrum of product 3ca is shown in Figure 21 , and the 13C NMR spectrum is shown in Figure 22 .

[0129] Example 11: Scaling-up process

[0130] Weigh successively 5-(3-phenylpropyl)-5H-dithioxanthene 5-ium trifluoromethanesulfonate (1.0 mmol, 1.0 equiv.), 4-methoxyphenylacetylene (1.2 mmol, 1.2 equiv.), 4,7-diphenyl-1,10-phenanthroline (0.12 mmol, 0.12 equiv.), copper(II) 2-thiophenecarboxylate (0.1 mmol, 0.10 equiv.), potassium carbonate (3.0 mmol, 3.0 equiv.). Dissolve the above substances in 5.0 mL of acetonitrile and 5.0 mL of methanol solution, and stir well to dissolve to obtain a mixed solution. Transfer the mixed solution to a syringe, and use an infusion pump to pump it into the microfluidic reactor (with a volume of 2.0 mL) of the microfluidic reaction device at a flow rate of 0.1 mL / min for a photoreaction at room temperature (blue light of 450 nm - 455 nm). The residence time of the photoreaction in the microfluidic reactor is 20 min. Collect the effluent and monitor it by TLC. Quench the reaction after the reaction is completed, and then extract the reaction solution with dichloromethane and saturated brine (3 × 125 mL). Combine the organic layers, dry with anhydrous sodium sulfate, distill off the solvent under reduced pressure, and obtain product 3aa, 235 mg, with a separation yield of 94% by silica gel column chromatography (petroleum ether: ethyl acetate).

[0131] Example 12: Screening of ligands

[0132] The experimental method was the same as that of Example 1, except that the ligand 4,7-diphenyl-1,10-phenanthroline was replaced with 2,2'-bipyridine, 3,2':6',3”-terpyridine, and 1,10-phenanthroline. The yields of the finally prepared product 3aa are shown in Table 1.

[0133] Table 1

[0134] Ligand Isolated Yield of Product 3aa 4,7-Diphenyl-1,10-phenanthroline 94％ 2,2'-Bipyridine 49％ 3,2':6',3”-Terpyridine 52％ 1,10-Phenanthroline 18％

[0135] Example 13: Screening of copper catalysts

[0136] The experimental method was the same as that of Example 1, except that the copper catalyst was replaced with copper bromide, cuprous bromide, copper chloride, cuprous chloride, copper acetylacetonate, copper oxide, copper acetate, copper trifluoromethanesulfonate, copper nitrate, copper diphenylphosphite, and copper sulfate. The yields of the finally prepared product 3aa are shown in Table 2.

[0137] Table 2

[0138]

[0139]

[0140] Example 14: Screening of solvents

[0141] The experimental method was the same as that of Example 1, except that the solvents 1.0 mL of acetonitrile and 1.0 mL of methanol were replaced with 1.0 mL of dichloromethane + 1.0 mL of methanol, 1.0 mL of dimethyl sulfoxide + 1.0 mL of acetonitrile, 1.0 mL of N,N-dimethylformamide + 1.0 mL of ethanol, 2.0 mL of tetrahydrofuran, 1.0 mL of ethyl acetate + 1.0 mL of dichloromethane, 2.0 mL of 1,2-dichloroethane, 1.0 mL of 1,4-dioxane + 1.0 mL of toluene, and 1.0 mL of acetone + 1.0 mL of water. The yields of the finally prepared product 3aa are shown in Table 3.

[0142] Table 3

[0143] Solvent Isolated Yield of Product 3aa 1.0 mL Acetonitrile + 1.0 mL Methanol 94％ 1.0 mL Dichloromethane + 1.0 mL Methanol 46％ 1.0 mL Dimethyl Sulfoxide + 1.0 mL Acetonitrile 35％ 1.0 mL N,N-Dimethylformamide + 1.0 mL Ethanol 21％ 2.0 mL Tetrahydrofuran 68％ 1.0 mL Ethyl Acetate + 1.0 mL Dichloromethane 33％ 2.0 mL 1,2-Dichloroethane 39％ 1.0 mL 1,4-Dioxane + 1.0 mL Toluene 57％ 1.0 mL Acetone + 1.0 mL Water 24％

[0144] Comparative Example 1:

[0145]

[0146] Weigh successively 5-(3-phenylpropyl)-5H-dithioxanthene 5-ium trifluoromethanesulfonate (0.20 mmol, 1.0 equiv.), p-methoxyphenylacetylene (0.24 mmol, 1.2 equiv.), 4,7-diphenyl-1,10-phenanthroline (0.024 mmol, 0.12 equiv.), copper(II) thiophene-2-carboxylate (0.02 mmol, 0.10 equiv.), potassium carbonate (0.60 mmol, 3.0 equiv.). Dissolve the above substances in 1.0 mL of acetonitrile and 1.0 mL of methanol solution, and stir well to dissolve them to obtain a mixed solution. Transfer the mixed solution to a visible light reaction device (blue light at 450 nm - 455 nm) and irradiate it for a photochemical reaction at room temperature for 6 hours. After the reaction is completed, quench the reaction, then extract the reaction solution with dichloromethane 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, 36.5 mg, with a yield of 73% by silica gel column chromatography (petroleum ether: ethyl acetate).

[0147] The present invention provides an idea and method for realizing the cross-coupling of alkylthioxanthenium salts and terminal alkynes through the synergistic catalysis of visible light and copper. 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 specified in this embodiment can be realized by the prior art.

Claims

1. A method for the cross - coupling of alkylthianthrenium salts with terminal alkynes by the synergistic catalysis of visible light and copper, which is characterized in that, Mix the alkylthianthrenium salt compound 1 with the phenylacetylene compound 2, ligand, copper catalyst, base, and solvent to obtain a mixed solution; pump the mixed solution into the microfluidic reactor of the microfluidic reaction device for a photoreaction to obtain the terminal alkyne alkylation product 3; Among them, the structure of the alkylthianthrenium salt compound 1 is shown in Formula 1, the structure of the phenylacetylene compound 2 is shown in Formula 2, and the structure of the terminal alkyne alkylation product 3 is shown in Formula 3: n is an integer between 1 and 6; m is an integer between 0 and 5; R1 is selected from halogen, substituted or unsubstituted phenyl, substituted or unsubstituted benzyloxy, substituted or unsubstituted thiophenyl, substituted or unsubstituted C1-C4 alkoxy, or substituted or unsubstituted adamantyl; R2 is selected from halogen, substituted or unsubstituted C1-C4 alkoxy, methoxycarbonyl, trifluoromethyl or ethoxycarbonyl; Among them, the substitution is selected from being substituted by 1 to 3 identical or different substituents; the substituents are halogen.

2. The method according to claim 1, wherein n is an integer between 1 and 4; m is an integer between 1 and 2; R1 is selected from fluorine, chlorine, bromine, substituted or unsubstituted phenyl, benzyloxy, thiophenyl, C1-C2 alkoxy or adamantyl; R2 is selected from fluorine, chlorine, bromine, C1-C2 alkoxy or methoxycarbonyl; Among them, the substitution is selected from being substituted by 1 to 3 identical or different substituents; the substituents are fluorine, chlorine or bromine.

3. The method according to claim 1, wherein The ligand is 4,7-diphenyl-1,10-phenanthroline; and / or, the copper catalyst is copper thiophene-2-carboxylate; and / or, the base is any one or a combination of triethylamine, potassium carbonate, sodium carbonate, sodium bicarbonate, tetramethylethylenediamine, 4-dimethylaminopyridine and 2,6-dimethylpyridine; and / or, the solvent is any one or a combination of acetonitrile and methanol.

4. The method according to claim 1, wherein The ligand is 4,7-diphenyl-1,10-phenanthroline; and / or, the copper catalyst is copper thiophene-2-carboxylate; and / or, the solvent is a mixture of acetonitrile and methanol with a volume ratio of (1.0-2.0):(1.0-2.0).

5. The method according to claim 1, wherein The molar ratio of the alkylthianthrenium salt compound 1 to the phenylacetylene compound 2 is (1.0-2.0):(1.0-2.0); and / or, the molar ratio of the alkylthianthrenium salt compound 1 to the ligand is (5.0-10.0):1.0; and / or, the molar ratio of the alkylthianthrenium salt compound 1 to the copper catalyst is (5.0-15.0):1.0; and / or, the molar ratio of the alkylthianthrenium salt compound 1 to the base is 1.0:(1.0-5.0).

6. The method according to claim 1, characterized in that, In the mixed solution, the concentration of the alkylthianthrenium salt compound 1 is 0.01 mmol / mL to 0.50 mmol / mL.

7. The method according to claim 1, wherein For the photoreaction, the reaction temperature is room temperature; and / or, the residence time of the photoreaction in the microfluidic reactor is 10 min to 60 min.

8. The method according to claim 1, characterized in that In the photoreaction, the wavelength of the light is 360 nm to 600 nm.

9. The method according to claim 1, wherein The microfluidic reaction device includes a connecting pipeline, a feed pump, a microfluidic reactor, a light source, and a receiver; wherein, the feed pump, the microfluidic reactor, and the receiver are connected in series through pipelines in sequence.

10. The method according to claim 9, wherein The light source is located outside the microfluidic reactor, and its illumination range covers the microfluidic reactor.

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