A green synthesis method of internal alkyne compounds

Abstract

The invention discloses a green synthesis method of an internal alkyne compound. Alkyne compounds and 4-substituted hans ester are added to a solvent, and a light reaction is carried out in the presence of a photocatalyst and a base. After the reaction is completed, the reaction mixture is separated and purified to obtain the internal alkyne compound. The invention provides a rapid synthesis method of an internal alkyne compound, which can realize simple operation and mild reaction conditions in the whole production route process, and the raw materials and solvents used in the whole process are low in price, which is conducive to cost control.

Description

(I) Technical field

[0001] The invention relates to the technical field of organic chemical synthesis, in particular to a rapid green synthesis method of an internal alkyne compound. (II) Background technology

[0002] Alkynes are one of the most fundamental building blocks in synthetic chemistry. They play a ubiquitous role as substrates in various catalytic processes, as key pharmacophores in bioactive molecules, in bioconjugation and in materials science, as the alkyne group is not only a versatile building block, but also an important structural motif and ubiquitous intermediate in the synthesis of fine chemicals, drugs and polymer optoelectronic materials. This makes this functional group an indispensable tool in the toolbox of synthetic chemists. Therefore, the development of new methods is of great significance for the synthesis of natural products or drug molecules with internal alkynes.

[0003] In 2016, Doug E. Frantz et al. synthesized internal alkynes by decarboxylation / elimination tandem reaction of trifluoromethanesulfonic acid enol under the catalysis of Pd2(dba)3 (Org. Lett. 2016, 18, 3937-3939). In 2013, Jin-Heng Li et al. synthesized methyl functionalized internal alkynes using sulfonium ylides as substrates and phenylacetylene compounds under the catalysis of Pd(MeCN)2Cl2 (J. Org. Chem. 2013, 78, 10421-10426). The above reactions all used palladium metal as a catalyst, and the reaction conditions were harsh and the operation was complicated.

[0004] In 2015, Yong-Qiang Wang et al. synthesized alkynes through the free radical reaction of N-tosylhydrazone catalyzed by copper (Org. Lett. 2015, 17, 1692-1695). In 2017, Shinya Harusawa et al. used TMSN3 and Bu2SnO as catalysts in toluene to directly produce the corresponding internal alkynes by treating ketone-derived methyl phosphine under reflux (J. Org. Chem. 2017, 82, 5538-5556). Although the above reactions do not use expensive metals as catalysts, the reaction substrates are complex and the operation requirements are high.

[0005] Therefore, it is necessary to develop a synthetic method with mild reaction conditions, simple operation and high yield. (III) Summary of the invention

[0006] The present invention aims to provide a green synthesis method of an internal alkyne compound with mild reaction conditions, simple operation and high yield. The green and pollution-free preparation method is adopted to replace the current traditional metal catalysis, and the problems of complex operation and large amount of catalyst used in the synthesis of alkynes are solved.

[0007] The technical solution adopted by the present invention is:

[0008] The present invention provides a green synthesis method of an internal alkyne compound represented by formula (I), the method comprising the following steps: adding an alkyne compound represented by formula (II) and a 4-substituted hans ester represented by formula (III) into a solvent, and performing a light irradiation reaction in the presence of a photocatalyst and a base. After the reaction is completed, the reaction mixture is separated and purified to obtain the internal alkyne compound represented by formula (I);

[0009] The solvent is selected from at least one of toluene, 1,4-dioxane, tetrahydrofuran, dichloromethane, acetonitrile and dichloroethane; the solvent is preferably acetonitrile or dichloromethane, more preferably dichloromethane;

[0010] The photocatalyst is selected from Ir[dF(CF3)ppy]2(dtbbpy)PF6 (bis[2-(2,4-difluorophenyl)-5-trifluoromethylpyridine][2-2-bi(4-tert-butylpyridine)]iridium di(hexafluorophosphate) salt), Eosin Y (2', 4', 5', 7'-tetrabromofluorescein), Ru (bpy) 3 Cl2 · 6H2O (terpyridyl ruthenium chloride hexahydrate), Ir (ppy) 2 (dtbbpy) PF6 ((4, 4'-di-tert-butyl-2, 2'-bipyridyl) bis [(2-pyridyl) phenyl] iridium (III) hexafluorophosphate), Ir (ppy) 3 (tris (2-phenylpyridine) iridium (III)), copper-based photosensitizer PS1, copper-based photosensitizer PS2, copper-based photosensitizer PS3, copper-based photosensitizer PS4, copper-based photosensitizer PS5, copper-based photosensitizer PS6, copper-based photosensitizer PS7, 4CzIPN (2, 4, 5, 6-tetra (9H-carbazole-9-yl) isophthalonitrile) at least one; the photocatalyst is preferably PS1 or PS6, more preferably PS1;

[0011]

[0012]

[0013] The base is selected from at least one of Na2CO3, K2CO3, K2HPO4, NaOAc, K3PO4, and t-BuONa; the base is preferably Na2CO3 or K3PO4, more preferably K3PO4;

[0014]

[0015] In formula (II), R 1 is monosubstituted or polysubstituted, the R 1R is hydrogen, C1-C6 alkyl, halogen, ester group, trifluoromethyl, the ester group includes methyl formate, methoxycarbonyl (-COOMe), ethoxycarbonyl (-COOEt), halogen includes fluorine (F), chlorine (Cl), bromine (Br); more preferably hydrogen, 1-methyl formate, or 1-bromine; R 2 is sulfonemethyl (-SO2Me), bromine, chloride or sulfoneethyl, preferably sulfonemethyl or;

[0016] Formula (III) R 3 is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, benzyl or tert-butyl, preferably cyclopentyl or cyclohexyl, more preferably cyclohexyl;

[0017] In formula (I), R 1 Same as R in formula (II) 1 In formula (I), R 3 Same as R in formula (III) 3 .

[0018] Preferably, the molar ratio of the alkyne compound represented by formula (II) to the 4-substituted hans ester represented by formula (III), the photocatalyst and the base is 1:1-5:0.01-0.1:1-5, more preferably 1:1.5:0.05:3.

[0019] Preferably, the volume amount of the solvent is 15-25 mL / mmol, more preferably 20 mL / mmol, based on the molar amount of the alkyne compound represented by formula (II).

[0020] Preferably, the illumination reaction is carried out at room temperature (25° C.) and 15W illumination for 24 hours; the light source used in the illumination reaction is a 15W blue LED lamp, a 15W green LED lamp, or a 15W white LED lamp, and more preferably a 15W blue LED lamp. The illumination reaction is carried out under stirring at room temperature, and the reaction is completed by TLC monitoring, and the developing solvent is pure petroleum ether.

[0021] Preferably, the method for separating and purifying the reaction mixture is as follows: using petroleum ether:ethyl acetate in a volume ratio of 5:1 as a developing solvent for TLC monitoring; after the reaction is completed, the reaction solution is vacuum concentrated to 10-25% of the original volume, and then loaded onto a silica column (preferably with a column height of 300 mm and a diameter of 30 mm), and purified using petroleum ether as an eluting reagent, with an elution rate of 2 mL / min and an elution volume of 3-5 column volumes; collecting the eluate with an Rf of 0.5-0.8, and concentrating to dryness under reduced pressure to obtain an internal alkyne compound represented by formula (I).

[0022] The synthesis of the raw material (methylsulfonyl)ethynyl)benzene described in formula (II) of the present invention can refer to the literature [Org.Lett.2021,23,2243-2247], and the specific synthesis method is:

[0023] Step 1: Under an inert atmosphere (argon), the compound represented by formula (VI) and NaI are added to an oven-dried three-necked round-bottom flask, anhydrous acetonitrile a is added to form a suspension, and the suspension is bubbled with argon for 10 minutes; while maintaining vigorous stirring, alkyne (IV) is added through a syringe, and then anhydrous acetonitrile b with cerium ammonium nitrate (CAN) is added dropwise through a constant pressure dropping funnel; the suspension turns dark red and turns bright yellow after 4 hours, and TLC monitoring is performed using petroleum ether:ethyl acetate in a volume ratio of 5:1 as a developing solvent. After the reaction is completed, a saturated sodium chloride aqueous solution is added for quenching; then, it is extracted with dichloromethane; the organic phase is washed with a saturated sodium chloride aqueous solution (3×30 mL), dried with Na2SO4 and the solvent is removed, and concentrated to dryness under reduced pressure. These products are usually obtained as a fluffy solid and purified by column chromatography (silica column, V petroleum ether: V ethyl acetate in the elution reagent = 5:1), elution rate 4ml / min, elution volume 40 column volumes, collect the effluent below the Rf value of 0.3, and concentrate to dryness under reduced pressure to obtain the product; the ratio of the amount of the compound represented by formula (VI) to the amount of NaI feed material is 1:1; the volume of anhydrous acetonitrile a is 5mL / mmol based on the amount of the compound represented by formula (VI); the ratio of the amount of the compound represented by formula (VI) to the amount of alkyne (IV) feed material is 3:2.5; the ratio of the amount of CAN to the compound represented by formula (VI) feed material is 6.25:3; the volume of anhydrous acetonitrile b is 8.3mL / mmol based on the amount of the compound represented by formula (VI);

[0024] Step 2: The product of step 1 is then dissolved in Me2CO3, K2CO3 is added, heated to reflux, and the reaction is monitored by TLC with a volume ratio of 5:1 petroleum ether: ethyl acetate as a developing solvent. The reaction is completed, filtered, the carbonate is filtered off, and the filtrate is subjected to rotary evaporation to remove acetone. The crude product is purified by column chromatography (silica column, V petroleum ether: V ethyl acetate = 8:1 as eluent), the elution rate is 4 ml / min, the elution volume is 30-40 column volumes, and the eluent with an Rf value of 0.1-0.15 is collected, and concentrated to dryness under reduced pressure to obtain (methylsulfonyl)ethynyl)benzene shown in formula (II); the volume amount of Me2CO is 8.3 mL / mmol based on the amount of the compound shown in formula (VI); the ratio of the amount of K2CO3 to the amount of the compound shown in formula (VI) is 1.5:1;

[0025] The reaction equation for synthesizing compound (II) is as follows:

[0026]

[0027] Formula (IV) R 1 is monosubstituted or polysubstituted, the R 1R is hydrogen, C1-C6 alkyl, halogen, ester group, trifluoromethyl or nitro, the ester group includes methyl formate, methoxycarbonyl (-COOMe), ethoxycarbonyl (-COOEt), halogen includes fluorine (F), chlorine (Cl), bromine (Br); more preferably hydrogen, 1-methyl formate, or 1-bromine; R 2 is sulfonemethyl (-SO2Me), bromine, chloride or sulfoneethyl, preferably sulfonemethyl or;

[0028] In formula (VI), R 2 is sulfonemethyl, bromine, chloride or sulfoneethyl, preferably sulfonemethyl;

[0029] In formula (II), R 1 Same as R in formula (IV) 1 ; R in formula (II) 2 Same as R in formula (VI) 2 .

[0030] The synthesis of the raw material 4-substituted Hans ester of formula (III) of the present invention can refer to the literature [J.Am.Chem.Soc.2019,141,18230-18237]. The specific synthesis method is: add Bu4NHSO4 to a mixture of (Z)-3-aminobut-2-enoate, ethyl acetoacetate and the corresponding aldehyde (V) in ethylene glycol. The mixture is heated to 85°C for 4 hours under an argon atmosphere. The reaction is monitored by TLC, and the developing solvent is a volume ratio of petroleum ether: ethyl acetate = 10:1. After the reaction is completed, the mixture is cooled to room temperature, diluted with ethyl acetate and water, and the aqueous phase is extracted with ethyl acetate. The combined organic layer is washed with water and a saturated sodium chloride aqueous solution. The organic layer is dried over Na2SO4, filtered and concentrated to dryness under vacuum to obtain a crude product. The crude product is purified by silica column chromatography, using V petroleum ether: V ethyl acetate = 10:1 as eluent, elution rate 4 ml / min, elution volume 20-40 column volumes, collecting the eluent with an Rf value of 0.2, and concentrating to dryness under reduced pressure to obtain the desired product 4-substituted Hans ester; the molar ratio of the (Z)-3-aminobut-2-enoate to ethyl acetoacetate and aldehyde (V) is 1:1:1; the volumetric amount of ethylene glycol is 0.4 mL / mmol based on the amount of (Z)-3-aminobut-2-enoate; the molar ratio of Bu4NHSO4 to (Z)-3-aminobut-2-enoate is 0.12:1.

[0031] The reaction equation for synthesizing compound (III) is as follows:

[0032]

[0033] In formula (V), R 3is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, benzyl or tert-butyl, preferably cyclopentyl or cyclohexyl, more preferably cyclohexyl; in formula (III), R 3 Same as R in formula (V) 3 .

[0034] Compared with the prior art, the beneficial effects of the present invention are as follows: the present invention provides a green synthesis method for an internal alkyne compound, which can realize simple operation in the entire production route, mild reaction conditions (25°C), and the raw materials and solvents used in the entire process are low in price, which is conducive to cost control, and the product yield is increased to 92%. (IV) Description of the drawings

[0035] Figure 1 These are the hydrogen spectrum (A) and carbon spectrum (B) of 1-bromo-3-(cyclohexylethynyl)benzene.

[0036] Figure 2 These are the hydrogen spectrum (A) and carbon spectrum (B) of methyl 4-(cyclohexylethynyl)benzoate.

[0037] Figure 3 These are the hydrogen spectrum (A) and carbon spectrum (B) of 1-(2-cyclohexylethynyl)benzene.

[0038] Figure 4 These are the hydrogen spectrum (A) and carbon spectrum (B) of 1-(2-cyclopentylethynyl)benzene. (V) Specific implementation methods

[0039] The present invention is further described below in conjunction with specific embodiments, but the protection scope of the present invention is not limited thereto:

[0040] The synthesis of (methylsulfonyl)ethynyl)benzene shown in the raw material formula (II) in the embodiment of the present invention can refer to the literature [Org.Lett.2021,23,2243-2247], and the synthesis of 4-substituted hans ester shown in the raw material formula (III) can refer to the literature [J.Am.Chem.Soc.2019,141,18230-18237].

[0041] The silica column used in the embodiment of the present invention has a height of 500 mm and a diameter of 50 mm.

[0042] Example 1: Synthesis of 1-bromo-3-(cyclohexylethynyl)benzene (I-1)

[0043] 1. Synthesis of 1-bromo-3-(methylsulfonyl)ethynyl)benzene (Ⅱ-1)

[0044] The reaction formula is as follows:

[0045]

[0046] (1) Under an inert atmosphere (argon), 1.1 g (9.0 mmol) of sodium methanesulfinate (VI-1) and 1.4 g (9.0 mmol) of NaI were added to a 500 mL three-necked round-bottom flask dried in an oven, and then 45 mL of anhydrous acetonitrile (MeCN) was added. Argon was bubbled into the reaction solution for 10 minutes. While maintaining vigorous stirring, 1.4 g (7.5 mmol) of 1-bromo-3-ethynylbenzene (IV-1) was added by syringe, and then 75 mL of anhydrous acetonitrile solution containing 10.2 g (18.75 mmol) of cerium ammonium nitrate (CAN) was added dropwise through a constant pressure dropping funnel. The solution changed from colorless to dark red, and after 4 hours, it became bright yellow. Samples were taken and TLC detection was performed using petroleum ether:ethyl acetate in a volume ratio of 5:1 as the developing solvent. After the reaction was completed, 150 mL of saturated NaCl aqueous solution was used for quenching. Then, 600 mL of dichloromethane was used for extraction. The organic phase was washed with a saturated aqueous sodium chloride solution (3×30 mL), dried over Na2SO4 and the solvent was removed. The mixture was concentrated under reduced pressure and then spin-dried. The mixture was applied to a silica column for chromatography. The eluent was V petroleum ether: V ethyl acetate = 5:1. The elution rate was 4 ml / min and the elution volume was 1000 ml (40 column volumes). 500 ml of the eluate with an Rf value of 0.2 was collected and concentrated to dryness under reduced pressure to obtain 2.18 g of the product with a yield of 75%.

[0047] (2) 2.18 g of the product of step (1) was dissolved in 75 mL of Me2CO, and 1.9 g (13.5 mmol) of K2CO3 was added, heated to reflux, and TLC monitoring was performed using petroleum ether:ethyl acetate in a volume ratio of 5:1 as a developing solvent. Once the reaction was completed, the reaction solution was filtered, the carbonate was filtered off, and the filtrate was concentrated by vacuum to obtain a concentrate; the concentrate was loaded onto a silica column for chromatography, using V petroleum ether:V ethyl acetate = 8:1 as an eluent, an elution rate of 4 ml / min, an elution volume of 1000 ml (40 column volumes), and 500 ml of the eluate with an Rf value of 0.1 was collected to obtain 0.82 g of 1-bromo-3-(methylsulfonyl)ethynyl)benzene (II-1), with a yield of 56%.

[0048] 2. Synthesis of 4-cyclohexyl hensyl ester

[0049] The reaction formula is as follows:

[0050]

[0051] 4.1 g Bu4NHSO4 (1.2 mmol) was added to a mixture of 1.3 g (10 mmol) (Z)-3-aminobut-2-enoate, 1.3 g (10 mmol) ethyl acetoacetate and 1.1 g (10 mmol) cyclohexylcarboxaldehyde (V-1) in 4 ml ethylene glycol. The mixture was heated to 85 ° C for 4 hours under an argon atmosphere. The reaction was monitored by TLC, and the developing solvent was petroleum ether: ethyl acetate = 10:1, volume ratio. After the reaction was completed, the mixture was cooled to room temperature, diluted with 4 mL ethyl acetate and 16 mL water, and the aqueous phase was extracted with ethyl acetate (3×12 mL). The combined organic layer was washed with a saturated sodium chloride aqueous solution. The organic layer was dried over Na2SO4, filtered and concentrated to dryness under vacuum to obtain a crude product. The crude product was loaded onto a silica column for chromatography with V petroleum ether: V ethyl acetate = 10:1 as the eluent, elution rate 4 ml / min, elution volume 500 ml (20 column volumes), 200 ml of the eluent with an Rf value of 0.2 was collected, and concentrated to dryness under reduced pressure to obtain 2.28 g of a white solid, i.e. 4-cyclohexyl hensyl ester (III-1), with a yield of 68%.

[0052] 3. Synthesis of 1-bromo-3-(cyclohexylethynyl)benzene (Ⅰ-1)

[0053] The reaction formula is as follows:

[0054]

[0055] 52 mg (0.2 mmol) of 1-bromo-3-(methylsulfonyl)ethynyl)benzene (II-1), 101 mg (0.3 mmol) of 4-cyclohexyl hensyl ester (III-1), 127 mg K3PO4 (0.5mmol) and 11mg (0.01mmol) PS1 were added to a sealed tube, protected by argon, and then 4ml of dichloromethane was added. The reaction was carried out at 25°C under 15W LED blue light for 24h. After the reaction was completed, the reaction solution was concentrated in vacuo to 2ml, and then loaded onto a silica column. Purification was carried out using petroleum ether as an eluting agent at an elution rate of 2ml / min and an elution volume of 100ml (5 column volumes). 75ml of the eluate with an Rf value of 0.8 was collected and concentrated to dryness under reduced pressure to obtain 42.1mg of the product, i.e., 1-bromo-3-(cyclohexylethynyl)benzene (Ⅰ-1). The hydrogen and carbon spectra were shown in Figure 1 As shown, white oily liquid, yield 80%.

[0056] 1H NMR (400MHz, CDCl3): δ7.57(s,1H),7.41(d,J=7.8Hz,1H),7.34(d,J=7.8Hz,1H),7.18-7.14(m,1H ),2.63-2.57(m,1H),1.93-1.86(m,2H),1.79-1.76(m,2H),1.59-1.53(m,3H),1.40-1.34(m,3H); 13 C NMR (101MHz, CDCl3): δ134.39,130.56,130.12,129.57,126.20,121.98,96.01,79.19,32.56,29.62,25.89,24.86.

[0057] Example 2: Synthesis of methyl 4-(cyclohexylethynyl)benzoate (I-2)

[0058] The reaction formula is as follows:

[0059]

[0060] (1) Methyl 4-((methylsulfonyl)ethynyl)benzoate (II-2)

[0061] Same as Example 1, except that 1-bromo-3-ethynylbenzene was replaced with 1-methylformate-4-ethynylbenzene, and other operations were the same to obtain 1.1 g of methyl 4-((methylsulfonyl)ethynyl)benzoate (II-2);

[0062] (2) 4-Cyclohexyl Hans ester (III-1)

[0063] Prepared by the method of Example 1.

[0064] (3) Methyl 4-(cyclohexylethynyl)benzoate (Ⅰ-2)

[0065] The raw materials were 48 mg (0.2 mmol) of methyl 4-((methylsulfonyl)ethynyl)benzoate (II-2), 101 mg (0.3 mmol) of 4-cyclohexyl hensyl ester (III-1), 127 mg K3PO4 (0.6mmol) and 11mg copper-based photosensitizer PS1 (0.01mmol) were added to a sealed tube under argon protection, and then 4ml of dichloromethane was added. The reaction was carried out at 25°C and 15W LED blue light for 24h. After the reaction was completed, it was monitored by TLC (developing agent was petroleum ether: ethyl acetate = 5:1, volume ratio), and vacuum concentrated to 2ml. The silica column was loaded, and the elution reagent was petroleum ether. The elution rate was 2ml / min, and the elution volume was 100ml (5 column volumes). 75ml of the eluate with an Rf value of 0.5 was collected and concentrated to dryness under reduced pressure to obtain 44.1mg of the product, i.e., methyl 4-(cyclohexylethynyl)benzoate (Ⅰ-2). The hydrogen and carbon spectra were shown in Figure 2 As shown, white oily liquid, yield 91%.

[0066] 1 H NMR (400MHz, CDCl3): δ7.97(d,J=8.5Hz,2H),7.47(d,J=8.4Hz,2H),3.93(s,3H),2.65-2. 59(m,1H),1.92-1.89(m,2H),1.79-1.76(m,2H),1.58–1.55(m,3H),1.39–1.37(m,3H); 13C NMR (101MHz, CDCl3): δ166.71,131.49,129.36,129.02,128.74,97.93,80.08,52.12,32.53,29.70,25.87,24.87.

[0067] Example 3: Synthesis of 1-(2-cyclohexylethynyl)benzene (I-3)

[0068] The reaction formula is as follows:

[0069]

[0070] (1) (Methylsulfonyl)ethynyl)benzene (II-3)

[0071] The same method as in Example 1 was used, except that 1-bromo-3-ethynylbenzene was replaced by phenylacetylene. Other operations were the same to obtain 1.3 g of (methylsulfonyl)ethynyl)benzene (II-3).

[0072] (2) 4-Cyclohexyl Hans ester (III-1)

[0073] Prepared by the method of Example 1.

[0074] (3) 1-(2-cyclohexylethynyl)benzene (Ⅰ-3)

[0075] The raw material 36mg (0.2mmol) (methylsulfonyl) ethynyl) benzene (Ⅱ-3), 101mg (0.3mmol) 4-cyclohexyl hans ester (Ⅲ-1), 127mg K3PO4 (0.6mmol) and 11mg (0.01mmol) copper-based photosensitizer PS1 were added into a sealed tube under argon protection, and 4ml of dichloromethane was added. The reaction was carried out at 25℃ and 15W LED blue light for 24h. After the reaction was completed, it was monitored by TLC (developing agent was petroleum ether: ethyl acetate = 10:1, volume ratio). The mixture was concentrated in vacuo to 2ml and applied to a silica column for chromatography. The eluting agent was petroleum ether, the elution rate was 2ml / min, and the elution volume was 100ml (5 column volumes). 75ml of the eluate with an Rf value of 0.8 was collected and concentrated to dryness under reduced pressure to obtain 33.9mg of the product, i.e., 1-(2-cyclohexylethynyl) benzene (Ⅰ-3). The hydrogen and carbon spectra were shown in Figure 3 As shown, white oily liquid, yield 92%.

[0076] 1 H NMR (500MHz, CDCl3): δ7.41(d,J=1.6Hz,2H),7.32–7.27(m,3H),2.64-2.59(m,1 H),1.94–1.88(m,2H),1.82–1.76(m,2H),1.58-1.55(m,3H),1.40-1.36(m,3H); 13 C NMR (126MHz, CDCl3): δ131.57,128.13,127.38,124.17,94.45,80.53,32.73,29.67,25.95,24.90.

[0077] Under the same conditions, replacing the copper-based photosensitizer PS1, the yield of PS2 was 66%, the yield of PS3 was 77%, the yield of PS4 was 84%, the yield of PS5 was 63%, the yield of PS6 was 89%, the yield of PS7 was 72%, and the yield of Ir[dF(CF3)ppy]2(dtbbpy)PF6 (bis[2-(2,4-difluorophenyl)-5-trifluoromethylpyridine][2-2-bi(4-tert-butylpyridine)]iridium di(hexafluorophosphate) salt) was 80%.

[0078] Example 4: Synthesis of 1-(2-cyclopentylethynyl)benzene (I-4)

[0079] The reaction formula is as follows:

[0080]

[0081] (1) (Methylsulfonyl)ethynyl)benzene (II-4)

[0082] The same method as in Example 1 was used, except that 1-bromo-3-ethynylbenzene was replaced by phenylacetylene. Other operations were the same to obtain 1.3 g of (methylsulfonyl)ethynyl)benzene (II-4).

[0083] (2) 4-Cyclopentyl Hans ester (Ⅲ-2)

[0084] The same method as in Example 1 was used, except that cyclohexylcarboxaldehyde was replaced by cyclopentylcarboxaldehyde. Other operations were the same to obtain 2 g of 4-cyclopentyl hans ester.

[0085] (3) 1-(2-Cyclopentylethynyl)benzene (Ⅰ-4)

[0086] The raw material 36mg (0.2mmol) (methylsulfonyl) ethynyl) benzene (Ⅱ-4), 96mg (0.3mmol) 4-cyclopentyl hans ester (Ⅲ-2), 127mg K3PO4 (0.6mmol) and 11mg (0.01mmol) copper-based photosensitizer PS1 were added into a sealed tube under argon protection, and then 4ml of dichloromethane was added. The reaction was carried out at 25℃ and 15W LED blue light for 24h. After the reaction was completed, it was concentrated in vacuo to 2ml, and then loaded onto a silica column for chromatography. The eluting reagent was petroleum ether, the elution rate was 2ml / min, and the elution volume was 100ml (5 column volumes). 75ml of the eluate with an Rf value of 0.8 was collected and concentrated to dryness under reduced pressure to obtain 25.9mg of the product, i.e., 1-(2-cyclopentylethynyl) benzene (Ⅰ-4). The hydrogen and carbon spectra were shown in Figure 4 As shown, white oily liquid, yield 76%.

[0087] 1 H NMR (400MHz, CDCl3): δ7.44–7.40(m,2H),7.33–7.27(m,3H),2.89-2.81(m,1H),2.08–1.98(m,2H),1.85–1.70(m,4H),1.68–1.60(m,2H); 13 C NMR (101MHz, CDCl3): δ131.55,128.17,127.40,124.16,94.62,80.06,33.94,30.81,25.07.

[0088] Comparative Example 1: Synthesis of 1-(2-cyclohexylethynyl)benzene (4CzIPN as photocatalyst)

[0089]

[0090] The raw materials 36 mg (0.2 mmol) of (methylsulfonyl)ethynyl)benzene (Ⅱ-3), 101 mg (0.3 mmol) of 4-cyclohexyl hans ester (Ⅲ-1), 127 mg of K3PO4 (0.6 mmol) and 8 mg (0.01 mmol) of 4CzIPN were added into a sealed tube under argon protection, and then 4 ml of dichloromethane was added. The reaction was carried out at 25°C and 15W blue light for 24 hours. After the reaction was completed, it was monitored by TLC (developing agent was petroleum ether:ethyl acetate=10:1, volume ratio). The mixture was concentrated in vacuo to 2 ml and applied to a silica column for chromatography. The eluting reagent was petroleum ether, the elution rate was 2 ml / min, and the elution volume was 100 ml (5 column volumes). 75 ml of the eluate with an Rf value of 0.8 was collected and concentrated to dryness under reduced pressure to obtain 22.1 mg of the product, i.e., 1-(2-cyclohexylethynyl)benzene (Ⅰ-3), a white oily liquid with a yield of 60%.

[0091] Comparative Example 2: Synthesis of 1-(2-cyclohexylethynyl)benzene (1,4-dioxane as solvent)

[0092] The raw materials 36 mg (0.2 mmol) (methylsulfonyl) ethynyl) benzene (II-3), 101 mg (0.3 mmol) 4-cyclohexyl hensyl ester (III-1), 127 mg K3PO4 (0.6mmol) and 8mg (0.01mmol) of copper-based photosensitizer 4CzIPN were added to a sealed tube under argon protection, and then 4ml of 1,4-dioxane was added. The reaction was carried out at 25°C and 15W blue light for 24h. After the reaction was completed, it was monitored by TLC (developing agent was petroleum ether:ethyl acetate = 10:1, volume ratio). The mixture was concentrated in vacuo to 2ml and applied to a silica column for chromatography. The eluting reagent was petroleum ether, the elution rate was 2ml / min, and the elution volume was 100ml (5 column volumes). 75ml of the eluate with an Rf value of 0.8 was collected and concentrated to dryness under reduced pressure to obtain 22.1mg of the product, i.e., 1-(2-cyclohexylethynyl)benzene (Ⅰ-3), a white oily liquid with a yield of 60%.

[0093] Comparative Example 3: Synthesis of 1-(2-cyclohexylethynyl)benzene (NaOAc as base)

[0094] The raw material 36 mg (0.2 mmol) of (methylsulfonyl)ethynyl)benzene (Ⅱ-3), 101 mg (0.3 mmol) of 4-cyclohexyl hans ester (Ⅲ-1), 49.2 mg (0.6 mmol) of NaOAc and 11 mg (0.01 mmol) of copper-based photosensitizer PS1 were added into a sealed tube under argon protection, and then 4 ml of dichloromethane was added. The reaction was carried out at 25°C and 15W blue light irradiation for 24 hours. After the reaction was completed, it was monitored by TLC (developing agent was petroleum ether:ethyl acetate = 10:1, volume ratio). The mixture was concentrated in vacuo to 2 ml and applied to a silica column for chromatography. The eluting reagent was petroleum ether, the elution rate was 2 ml / min, and the elution volume was 100 ml (5 column volumes). 75 ml of the eluate with an Rf value of 0.8 was collected and concentrated to dryness under reduced pressure to obtain 29.5 mg of the product, 1-(2-cyclohexylethynyl)benzene (Ⅰ-3), a white oily liquid with a yield of 80%.

Claims

1. A green synthesis method of an internal alkyne compound, characterized in that: The method comprises the following steps: adding an alkyne compound represented by formula (II) and a 4-substituted hans ester represented by formula (III) into a solvent, and performing a light irradiation reaction in the presence of a photocatalyst and a base. After the reaction is completed, the reaction mixture is separated and purified to obtain an internal alkyne compound represented by formula (I); The solvent is selected from at least one of 1,4-dioxane, dichloromethane and dichloroethane; The base is selected from potassium phosphate or sodium acetate; The light source used in the illumination reaction is a 15W blue LED lamp; The photocatalyst is selected from at least one of copper-based photosensitizer PS1, copper-based photosensitizer PS2, copper-based photosensitizer PS3, copper-based photosensitizer PS4, copper-based photosensitizer PS5, copper-based photosensitizer PS6, and copper-based photosensitizer PS7; In formula (II), R 1 is monosubstituted or polysubstituted, the R 1 is hydrogen, C1-C6 alkyl, halogen, 1-methylformyl, trifluoromethyl; R 2 is sulfonemethyl; Formula (III) R 3 is cyclopropyl, cyclobutyl, cyclopentyl or tert-butyl; In formula (I), R 1 Same as R in formula (II) 1 In formula (I), R 3 Same as R in formula (III) 3 .

2. The green synthesis method of internal alkyne compounds as claimed in claim 1, characterized in that: The molar ratio of the alkyne compound represented by formula (II) to the 4-substituted hans ester represented by formula (III), the photocatalyst and the base is 1:1-5:0.01-0.1:1-5.

3. The green synthesis method of internal alkyne compounds as claimed in claim 1, characterized in that: The volume amount of the solvent is 15-25 mL / mmol based on the molar amount of the alkyne compound represented by formula (II).

4. The green synthesis method of internal alkyne compounds as claimed in claim 1, characterized in that: In formula (II), R 1 is hydrogen, 1-methylformate, or 1-bromo.

5. The green synthesis method of internal alkyne compounds as claimed in claim 1, characterized in that: The solvent is dichloromethane, the catalyst is copper-based photosensitizer PS1, and the base is K3PO4.

6. The green synthesis method of internal alkyne compounds according to claim 1, characterized in that: The light irradiation reaction was carried out at room temperature and 15W light for 24 hours.

7. The green synthesis method of internal alkyne compounds as claimed in claim 1, characterized in that: The method for separating and purifying the reaction mixture is as follows: using petroleum ether:ethyl acetate in a volume ratio of 5:1 as a developing agent for TLC monitoring; after the reaction is completed, the reaction solution is vacuum concentrated to 10-25% of the original volume; the reaction solution is then loaded onto a silica column; petroleum ether is used as an eluting agent for purification; the elution rate is 2 mL / min; the elution volume is 3-5 column volumes; the eluate under the condition of Rf value of 0.5-0.8 is collected; and the solution is concentrated to dryness under reduced pressure to obtain the internal alkyne compound represented by formula (I).

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