Method for preparing cyclic ether based on propargyl compound

Abstract

The invention discloses a method for preparing cyclic ether based on a propargyl compound. According to the method, in an organic solvent, propargyl alcohol ester is taken as a reaction substrate, palladium is taken as a catalyst, arylboronic acid is taken as an additive, and alkenylated cyclic ether or conjugated diene cyclic ether is divergently synthesized under different conditions. In the reaction, the propargyl alcohol ester is coordinated with the palladium catalyst, so that the target product cyclic ether is obtained with high yield and excellent selectivity. The synthesis method disclosed by the invention is simple, feasible and safe, the synthesis of the cyclic ether can be realized by starting from commercially available raw materials through three steps, the yield of the cyclic ether is up to 87% after combination with optimization of reaction conditions, and the method belongs to a universal, efficient, economic and environment-friendly cyclic ether synthesis method and has a good market prospect.

Description

Technical Field

[0001] The invention belongs to the fields of catalytic synthesis technology and fine chemical synthesis, and particularly relates to a method for preparing cyclic ether based on a propargyl compound. Background Art

[0002] Cyclic molecules are widely found in natural products and bioactive molecules, and play a very important role in organic synthesis. For example, Octalactin A has anticancer effects, (-)-isolaurallene has antibacterial activity, and (+)-Brasilenyne is a potent antifeedant. ， However, the synthesis of cyclic molecules is more difficult than that of other organic compounds due to unfavorable cross-ring interactions and entropic effects.

[0003] At present, the strategies for synthesizing cyclic molecules are very limited: intramolecular cyclization, ring expansion, and multi-component cyclization, and they have disadvantages such as harsh synthesis conditions, low yield, and small scope of application. Intramolecular cyclization is a common method for synthesizing cyclic molecules. Its advantages are that it is easier to react than intermolecular reactions, has fewer by-products, and has high yields. However, the traditional intramolecular cyclization strategy has disadvantages such as complex reaction substrate structures, cumbersome synthesis steps, poor reaction compatibility, and difficulty in controlling the chemical selectivity of intramolecular cyclization.

[0004] In 2015, Stuart L. Schreiber's group reported the use of alkynols to prepare medium-sized cyclic ethers. The reaction had a favorable yield, but the chemical selectivity was poor. In 2009, Vy M. Dong's group obtained benzocyclic ethers by modifying olefins on the benzene ring for intramolecular cyclization. However, since only some simple groups can be connected to the benzene ring, the substrate range is relatively limited. Therefore, it is very important to develop a method for synthesizing cyclic molecules with a simple substrate structure, good adaptability to reaction conditions, and the ability to control the production of a single product. Summary of the invention

[0005] In view of the shortcomings of the prior art, the object of the present invention is to provide a method for preparing cyclic ethers based on propargyl compounds. The method is based on palladium-catalyzed propargyl alcohol esters, and through the mode of oxidative addition reaction, the synthesis of olefinated cyclic ethers and conjugated dienated cyclic ethers is achieved with high stereoselectivity. The preparation method provides a simple, convenient, fast and efficient strategy for the synthesis of complex natural products and biologically active molecules.

[0006] In order to solve the problems of the prior art, the technical solution adopted by the present invention is:

[0007] A method for preparing a cyclic ether based on a propargyl compound, specifically comprising: in an organic solvent, using propargyl alcohol ester As raw materials, palladium as catalyst, arylboronic acid as additive, ligand L, and then react at 30-50 or 80-100°C for 10-20 hours to obtain

[0008] Wherein, R is a heteroaryl, furan, or thiophene group containing N, O, or S, which is unsubstituted or substituted at any position on the aromatic ring by a C1-C20 alkyl group, a C1-C20 alkylcarbonyl group, a C1-C20 alkylnitro group, a C1-C20 alkylcyano group, or a C1-C20 alkylcyano group;

[0009] The OPG is a C1-C20 alkyl carbonyl group;

[0010] n is an integer from 1 to 7.

[0011] As an improvement, the palladium is one or more of palladium acetate, palladium pivalate, tetrakistriphenylphosphine palladium, di(tri-tert-butylphosphine) palladium, tri(dicyclohexylphosphine)palladium dichloride, bis(tri-o-tolylphosphine)palladium dichloride, bis(methyldiphenylphosphine)palladium dichloride, bis(acetonitrile)palladium dichloride, bis(benzonitrile)palladium dichloride, bis(dibenzylideneacetone)palladium, and tris(dibenzylideneacetone)dipalladium.

[0012] As an improvement, the ligand L includes a bidentate P ligand or a monodentate chiral P ligand.

[0013] As an improvement, the organic solvent is at least one of toluene, dichloromethane, 1,2-dichloroethane, isopropyl ether, cyclopentyl methyl ether, ethylene glycol dimethyl ether, ethyl acetate, 1,4-dioxane or tetrahydrofuran.

[0014] As an improvement, the molar ratio of the propargyl alcohol ester, palladium and ligand L is 1:0.1-0.3:0.1-0.3.

[0015] As an improvement, the temperature is 30-50°C, the time is 10-20 hours, and the obtained product is

[0016] Among them, the reaction formula is:

[0017]

[0018] As an improvement, the reaction temperature is 80-100°C, the reaction time is 10-20 hours, and the obtained product is

[0019] Among them, the reaction formula is:

[0020]

[0021] As an improvement, propargyl alcohol ester The preparation method is:

[0022] Step 1, to a 50 mL reaction bottle, add propargyl alcohol (5.0 mmol, 1.00 equiv), tert-butyldimethylsilyl chloride (10.0 mmol, 2.00 equiv), imidazole (10.0 mmol, 2.00 equiv), and dichloromethane (25 mL, 0.2 M) in sequence, react at 20 ° C for 5 hours, quench with saturated ammonium chloride solution, extract with dichloromethane, and separate by chromatography to obtain propargyl ether;

[0023] Step 2, under nitrogen conditions, propargyl ether (4.8mmol, 1.00equiv) and tetrahydrofuran (17mL, 0.3M) were added to a 50mL reaction bottle in sequence, mixed evenly at 20°C, and n-butyl lithium was added dropwise in a 0°C environment. After reacting for 10 minutes, aldehyde (4.8mmol, 1.0equiv) was added dropwise, and then the reaction bottle was moved to 20°C for reaction for 1 hour. The reaction bottle was placed at 0°C, and acyl chloride (5.76mmol, 1.2equiv) was added dropwise. After moving to 20°C for reaction for 2 hours, the reaction was quenched with water, and then extracted with ethyl acetate, filtered with anhydrous sodium sulfate, and dried under vacuum. Tetrahydrofuran (25mL, 0.2M) was added, TABF solution (7.2mmol, 1.5equiv, 1M in THF) was added dropwise at 0°C, and then placed at 20°C for reaction for 1 hour. The reaction was quenched with saturated ammonium chloride solution, extracted with ethyl acetate, and separated by chromatography to obtain the target product propargyl alcohol ester.

[0024] Principle: The palladium catalyst of the present invention has the characteristics of high catalytic activity, strong selectivity and convenient catalyst preparation. During the reaction process, the target product is obtained with excellent yield and high chemical selectivity through the mode of oxidation addition of metal palladium and propargyl alcohol ester.

[0025] Beneficial effects:

[0026] Compared with the prior art, the method for preparing cyclic ethers based on propargyl compounds of the present invention has the following advantages:

[0027] (1) The present invention provides a method for preparing cyclic ethers based on propargyl compounds. Starting from commercially available raw materials, only three steps of reaction are required to obtain highly chemically selective cyclic ethers. The reaction conditions are mild, the selectivity is high, and the yield is high. The substrate functional groups have good compatibility and a wide range of applications. The method is a general, efficient, economical and environmentally friendly method for synthesizing cyclic ether compounds.

[0028] (2) The present invention adopts a completely new reaction mode to synthesize cyclic ethers: through an oxidative addition mode, it undergoes two key steps: a cyclobutene palladium intermediate and a Π-allyl palladium intermediate. This preparation method makes up for the shortcomings of the previous synthesis method, which has a single product structure and poor selectivity.

[0029] (3) The cyclic ether compounds synthesized by the method of the present invention are key intermediates for synthesizing drugs or bioactive molecules and have a wide application prospect in synthesizing drug molecules and natural compounds. DETAILED DESCRIPTION

[0030] The present invention can be better understood according to the following examples. However, it is easy for those skilled in the art to understand that the contents described in the examples are only used to illustrate the present invention, and should not and will not limit the present invention described in detail in the claims.

[0031] The experimental methods described in the examples are conventional methods unless otherwise specified; the reagents and materials described can be obtained from commercial sources or simply prepared by the following methods unless otherwise specified.

[0032] The method for synthesizing the substrate used in the present invention is prior art, and can be specifically performed by referring to the following steps:

[0033] To a 50 mL reaction bottle, propargyl alcohol (5.0 mmol, 1.00 equiv), tert-butyldimethylsilyl chloride (10.0 mmol, 2.00 equiv), imidazole (10.0 mmol, 2.00 equiv), and dichloromethane (25 mL, 0.2 M) were added in sequence. After reacting at 20 °C for 5 hours, the reaction was quenched with saturated ammonium chloride solution, and then extracted with dichloromethane. The propargyl ether was separated by chromatography.

[0034] Under nitrogen, propargyl ether (4.8 mmol, 1.00 equiv) and tetrahydrofuran (17 mL, 0.3 M) were added to a 50 mL reaction bottle in sequence. After mixing at 20°C, n-butyl lithium was added dropwise in a 0°C environment. After reacting for 10 minutes, aldehyde (4.8 mmol, 1.0 equiv) was added dropwise. The reaction bottle was then moved to 20°C for reaction for 1 hour. The reaction bottle was placed at 0°C and acyl chloride (5.76 mmol, 1.2 equiv) was added dropwise. After moving to 20°C for reaction for 2 hours, the reaction was quenched with water, extracted with ethyl acetate, filtered with anhydrous sodium sulfate, and dried under vacuum. Tetrahydrofuran (25 mL, 0.2 M) was added. TABF solution (7.2 mmol, 1.5 equiv, 1 M in THF) was added dropwise at 0°C and placed at 20°C for reaction for 1 hour. The reaction was quenched with saturated ammonium chloride solution, extracted with ethyl acetate, and separated by chromatography to obtain the target product propargyl alcohol ester.

[0035] The reaction formula is as follows:

[0036]

[0037] Example 1 Compound 1 Synthesis

[0038] Referring to the above-mentioned substrate synthesis method, the aldehyde is benzaldehyde, and the acyl chloride is trimethylacetyl chloride. The reaction is carried out to obtain a substrate 1: The NMR data are as follows:

[0039] 1 H NMR(400MHz,Chloroform-d)δ7.54–7.44(m,2H),7.40–7.30(m,3H),6.40(d,J=2.2Hz,1H),3. 63(t,J=6.4Hz,2H),2.34–2.21(m,2H),1.63–1.52(m,5H),1.47(m,J=6.7Hz,2H),1.21(s,9H). 13 C NMR (100 MHz, CDCl 3 ): δ177.45,137.87,128.50,127.28,87.76,65.86,62.56,38.77,32.10,28.15,26.99,24.93,18.78.HRMS(ESI):Calcd 302.4140forC 19 H 26 O 3 [M+H] + Found:303.4213.

[0040] Under nitrogen conditions, tetrakis(triphenylphosphine)palladium (0.03mmol), substrate 1 (0.3mmol), ligand L (dppf (0.033mmol), arylboronic acid (0.03mmol), potassium pivalate (0.075mmol) were added to a 25mL Shrek tube in sequence. ， Isopropyl ether (4 mL) and tetrahydrofuran (2 mL) were mixed evenly at room temperature, and the reaction mixture was reacted at 50° C. for 16 h. After the reaction was completed, direct chromatography separation (petroleum ether: ethyl acetate V / V=100:1) was performed to obtain compound 1 with a yield of 87%. 1 H NMR (400 MHz, CDCl 3)δ7.53(d,J=7.8Hz,2H),7.29(t,J=7.6Hz,2H),7.16(t,J=7.3Hz,1H),5.77(s,1H),5.51(d d,J=9.0,4.9Hz,1H),4.18–4.09(m,2H),1.97–1.88(m,2H),1.74–1.64(m,4H),1.24(s,9H). 13 C NMR (100 MHz, CDCl 3 ): δ175.84,148.95,137.87,137.68,134.74,130.27,129.84,128.85,128.32,128 .19,127.42,127.25,119.28,39.27,31.35,27.45,23.00,13.87.HRMS(ESI):Calcd 303.1955for C 19 H 26 O 3 [M+H] + Found:303.1946.

[0041] Example 2 Compound 2 Synthesis

[0042] Referring to the above-mentioned substrate synthesis method, the aldehyde is o-fluorobenzaldehyde, and the acyl chloride is trimethylacetyl chloride. The reaction is carried out to obtain the substrate 2. The NMR data are as follows:

[0043] 1 H NMR(400MHz,Chloroform-d)δ7.65(m,J=7.6,1.8Hz,1H),7.37–7.28(m,1H),7.17(m,J=7.6,1.2Hz,1H),7.05(m,J=9.6,8 .3,1.2Hz,1H),6.63(t,J=2.1Hz,1H),3.63(t,J=6.4Hz,2H),2.27(td,J=6.9,2.1Hz,2H),1.62–1.41(m,7H),1.20(s,9H). 13C NMR (101MHz, Chloroform-d) δ177.18, 160.28 (d, J = 250.1Hz), 130.54 (d, J = 8.2Hz), 129.31 (d, J = 3.2Hz), 125.16 (d, J = 13.2Hz), 124.22 (d, J = 3.7Hz), 115.67 (d, J = 21.0Hz), 88.05, 76.18, 62.83, 60.41 (d, J = 4.6Hz), 38.85, 32.25, 28.15, 27.07, 24.97, 18.86. 19 FNMR(376MHz,Chloroform-d)δ-117.74.HRMS(ESI):Calcd 321.1861for C 19 H 25 FO 3 [M+H] + Found:321.1860.

[0044] Under nitrogen conditions, tetrakis(triphenylphosphine)palladium (0.03mmol), substrate II (0.3mmol), ligand L (dppf (0.033mmol), arylboronic acid (0.03mmol), potassium pivalate (0.075mmol) were added to a 25mL Shrek tube in sequence. ， Isopropyl ether (4 mL) and tetrahydrofuran (2 mL) were mixed evenly at room temperature, and the reaction mixture was reacted at 50° C. for 16 h. After the reaction was completed, direct chromatography separation (petroleum ether: ethyl acetate V / V = 100: 1) was performed to obtain compound 2 with a yield of 81%. 1 H NMR(400MHz,Chloroform-d)δ7.97–7.89(m,1H),7.17–7.03(m,2H),7.03–6.94(m,1H),5.93(s,1H) ,5.55(dd,J=9.9,4.4Hz,1H),4.21–4.13(m,2H),2.04–1.87(m,2H),1.80–1.65(m,6H),1.25(s,9H). 13 C NMR (101MHz, Chloroform-d) δ177.43, 160.82, 158.36, 157.08 (d, J = 1.9Hz), 129.97 (d, J = 3.2Hz), 127.41 (d, J = 8.4Hz), 124.09–123.50(m),114.96(d,J=22.3Hz),98.85(d,J=6.7Hz),71.44,69.47,38.85,34.20,30.16,27.20,25.54,22.8719 F NMR(376MHz,Chloroform-d)δ-117.27.HRMS(ESI):Calcd 321.1861for C 19 H 25 FO 3 [M+H] + Found:321.1855.

[0045] Example 3 Compound 3 Synthesis

[0046] Referring to the above-mentioned substrate synthesis method, the aldehyde is m-fluorobenzaldehyde, and the acyl chloride is trimethylacetyl chloride. The reaction is carried out to obtain the substrate three. The NMR data are as follows:

[0047] 1 H NMR(400MHz,Chloroform-d)δ7.33(m,J=7.9,5.7Hz,1H),7.26–7.17(m,2H),7.02(m,J=8.3,2.6,1.1Hz,1H) ,6.39(t,J=2.1Hz,1H),3.64(t,J=6.5Hz,2H),2.28(td,J=6.9,2.1Hz,2H),1.63–1.41(m,7H),1.22(s,9H). 13 C NMR (101MHz, Chloroform-d) δ177.35, 162.88 (d, J = 246.3Hz), 140.52 (d, J = 7.0Hz), 130.16 (d, J = 8.1Hz), 123.00 (d, J = 3.0 Hz), 115.55 (d, J = 21.2Hz), 114.41 (d, J = 22.7Hz), 88.21, 65.18, 65.16, 62.90, 38.91, 32.30, 28.20, 27.11, 25.04, 18.88. 19 F NMR(376MHz,Chloroform-d)δ-112.63.HRMS(ESI):Calcd 321.1861for C 19 H 25 FO 3 [M+H] + Found:321.1867.

[0048] Under nitrogen conditions, tetrakis(triphenylphosphine)palladium (0.03mmol), substrate tris(0.3mmol), ligand L (dppf(0.033mmol), arylboronic acid (0.03mmol), potassium pivalate (0.075mmol) were added to a 25mL Shrek tube in sequence. ， Isopropyl ether (4 mL) and tetrahydrofuran (2 mL) were mixed at room temperature, and the reaction mixture was reacted at 50° C. for 16 h. After the reaction was completed, direct chromatography separation (petroleum ether: ethyl acetate V / V = 100: 1) was performed to obtain compound 3 with a yield of 78%. 1 H NMR(400MHz,Chloroform-d)δ8.00–7.87(m,1H),7.15–6.93(m,2H),5.92(s,1H),5.55(dd ,J=9.9,4.4Hz,1H),4.21–4.12(m,2H),2.02–1.86(m,2H),1.79–1.62(m,6H),1.25(s,9H). 13 C NMR (101MHz, Chloroform-d) δ177.45, 160.84, 158.38, 157.09 (d, J = 1.9Hz), 129.99 (d, J = 3.3Hz), 127.42 (d, J = 8.3Hz), 125.39–123.28(m),114.98(d,J=22.3Hz),98.89(d,J=6.7Hz),71.46,69.49,38.86,34.21,30.16,27.22,25.55,22.89. 19 F NMR(376MHz,Chloroform-d)δ-117.27HRMS(ESI):Calcd 321.1861for C 19 H 25 FO 3

[0049] [M+H] + Found:321.1852.

[0050] Example 4 Compound 4 Synthesis

[0051] Referring to the above-mentioned substrate synthesis method, the aldehyde is p-chlorobenzaldehyde, and the acyl chloride is trimethylacetyl chloride. The reaction is carried out to obtain the substrate four: The NMR data are as follows:

[0052] 1H NMR(400MHz,Chloroform-d)δ7.44–7.39(m,2H),7.33(d,J=8.5Hz,2H),6.36(t,J=2.1Hz,1H),3.64(t,J= 6.4Hz, 2H), 2.27 (td, J = 6.9, 2.1Hz, 2H), 1.56 (m, J = 7.0Hz, 5H), 1.46 (m, J = 12.9, 4.2Hz, 2H), 1.20 (s, 9H). 13 C NMR (101 MHz, CDCl 3 )δ177.40,136.64,134.53,128.88,128.83,88.21,76.95,65.26,62.90,38.88,32.28,28.21,27.09,25.04,18.89.HRMS(ESI):Calcd 354.1830for C 19 H 25 C1O 3 [M+NH 4 ] + Found:354.1834.

[0053] Under nitrogen conditions, tetrakis(triphenylphosphine)palladium (0.03mmol), substrate tetrakis (0.3mmol), ligand L is dppf (0.033mmol), arylboronic acid (0.03mmol), potassium pivalate (0.075mmol) were added in sequence to a 25mL Shrek tube. ， Isopropyl ether (4 mL) and tetrahydrofuran (2 mL) were mixed evenly at room temperature, and the reaction mixture was reacted at 50° C. for 16 h. After the reaction was completed, direct chromatography separation (petroleum ether: ethyl acetate V / V = 100: 1) was performed to obtain compound 4 with a yield of 92%. 1 H NMR(400MHz,Chloroform-d)δ7.46(d,J=6.6Hz,2H),7.28–7.20(d,2H),5.67(s,1H),5.52(d d,J=9.7,4.5Hz,1H),4.19–4.12(m,2H),2.01–1.82(m,2H),1.77–1.63(m,6H),1.24(s,9H). 13C NMR(101MHz,Chloroform-d)δ177.39,156.13,134.43,131.48,129.75,128.40,1 07.01,71.67,69.38,38.86,33.95,30.16,27.23,25.38,22.82.HRMS(ESI):Calcd 337.1565forC 19 H 25 C1O 3 [M+H] + Found:337.1560.

[0054] Example 5 Compound 5 Synthesis

[0055] Referring to the above-mentioned substrate synthesis method, the aldehyde is p-cyanobenzaldehyde, and the acyl chloride is trimethylacetyl chloride. The reaction is carried out to obtain the substrate 5. The NMR data are as follows:

[0056] 1 H NMR(400MHz,Chloroform-d)δ7.69–7.64(m,2H),7.59(d,J=8.5Hz,2H),6.41(t,J=2.2Hz,1H),3.6 3(t,J=6.4Hz,2H),2.27(td,J=6.9,2.1Hz,2H),1.61–1.52(m,5H),1.49–1.42(m,2H),1.21(s,9H). 13 C NMR (101 MHz, CDCl 3 )δ177.24,143.13,132.54,128.00,118.64,112.49,89.05,76.22,65.07,62.83,38.92,32.23,28.14,27.07,25.06,18.87.HRMS(ESI):Calcd 345.2172for C 20 H 25 NO 3

[0057] [M+NH 4 ] + Found:345.2175.

[0058] Under nitrogen conditions, tetrakis(triphenylphosphine)palladium (0.03mmol), substrate 5 (0.3mmol), ligand L (dppf (0.033mmol), arylboronic acid (0.03mmol), potassium pivalate (0.075mmol) were added to a 25mL Shrek tube in sequence.， Isopropyl ether (4 mL) and tetrahydrofuran (2 mL) were mixed at room temperature, and the reaction mixture was reacted at 50° C. for 16 h. After the reaction was completed, direct chromatography separation (petroleum ether: ethyl acetate V / V=20:1) was performed to obtain compound 5 with a yield of 64%. 1 H NMR(400MHz,Chloroform-d)δ7.60(d,J=2.0Hz,2H),7.53(d,J=8.5Hz,2H),5.61(d,J=7.2Hz,2H),4 .35–4.26(m,2H),2.06–1.93(m,1H),1.91–1.64(m,6H),1.55(dd,J=11.1,7.4Hz,1H),1.24(s,9H). 13 C NMR(101MHz,Chloroform-d)δ177.32,159.70,141.03,132.05,128.65,119.63,108.5 5,104.13,70.19,68.81,38.82,35.31,31.09,27.19,24.89,22.66.HRMS(ESI):Calcd 328.1907for C 20 H 25 NO 3 [M+H] + Found:328.1902.

[0059] Example 6 Compound 6 Synthesis

[0060] Referring to the above-mentioned substrate synthesis method, the aldehyde is p-methoxybenzaldehyde, and the acyl chloride is trimethylacetyl chloride. The reaction is carried out to obtain the substrate 6. The NMR data are as follows:

[0061] 1 H NMR(400MHz,Chloroform-d)δ7.44–7.40(m,2H),6.90–6.86(m,2H),6.35(t,J=2.2Hz,1H),3.81(s,3H),3.6 3(t,J=6.4Hz,2H),2.27(td,J=6.9,2.1Hz,2H),1.60–1.52(m,5H),1.48(dd,J=8.9,5.3Hz,2H),1.18(s,9H). 13 C NMR (101 MHz, CDCl 3)δ177.58,159.83,130.27,128.96,113.91,87.54,77.55,65.70,62.89,55.41,38.86,32.30,28.26,27.10,25.01,18.90.HRMS(ESI):Calcd 350.2326for C 20 H 28 O 4 [M+NH 4 + ;Found:350.2328

[0062] Under nitrogen, in a 25 mL Schlenk tube, palladium tetrakis(triphenylphosphine) (0.03 mmol), substrate six (0.3 mmol), ligand L as dppf (0.033 mmol), arylboronic acid (0.03 mmol), and potassium pivalate (0.075 mmol) were successively added ， Isopropyl ether (4 mL) and tetrahydrofuran (2 mL) were mixed evenly at room temperature, and the reaction mixture was reacted at 50 °C for 16 h. After the reaction was completed, it was directly separated by chromatography (petroleum ether:ethyl acetate V / V = 20:1) to obtain compound 6 with a yield of 64%. H NMR (400 MHz, Chloroform-d) δ 7.46 (d, J = 6.7 Hz, 2H), 6.84 (d, J = 6.9 Hz, 2H), 5.75 (s, 1H), 5.50–5.44 (m, 1H), 4.14–4.02 (m, 2H), 3.80 (s, 3H), 1.96–1.86 (m, 2H), 1.71–1.56 (m, 6H), 1.23 (s, 9H). 13 C NMR (101 MHz, Chloroform-d) δ 177.46, 158.15, 153.42, 129.85, 128.47, 113.78, 109.97, 73.08, 69.84, 55.37, 38.89, 32.83, 29.51, 27.26, 25.77, 23.03. HRMS(ESI):Calcd333.2061for C 20 H 28 O 4 [M+H] + ;Found:333.2062.

[0063] Example 7 Compound 7 Synthesis

[0064] Referring to the above substrate synthesis method, methyl p-formylbenzoate was used as the aldehyde and trimethylacetyl chloride was used as the acyl chloride for the reaction. The obtained substrate seven was The NMR data are as follows:​

[0065] 1 H NMR(400MHz,Chloroform-d)δ8.03(d,J=8.4Hz,2H),7.57–7.52(m,2H),6.43(t,J=2.1Hz,1H),3.91(s,3H ),3.63(t,J=6.5Hz,2H),2.27(td,J=6.9,2.1Hz,2H),1.60–1.52(m,5H),1.49–1.43(m,2H),1.21(s,9H). 13 C NMR (101 MHz, CDCl 3 )δ177.32,166.83,142.89,130.31,129.96,127.27,88.48,76.76,65.37, 62.85,52.32,38.90,32.26,28.18,27.09,25.03,18.89.HRMS(ESI):Calcd 378.2275for C 21 H 28 O 5 [M+NH 4 ] + Found:378.2269.

[0066] Under nitrogen conditions, tetrakis(triphenylphosphine)palladium (0.03mmol), substrate VII (0.3mmol), ligand L (dppf (0.033mmol), arylboronic acid (0.03mmol), potassium pivalate (0.075mmol) were added to a 25mL Shrek tube in sequence. ， Isopropyl ether (4 mL) and tetrahydrofuran (2 mL) were mixed evenly at room temperature, and the reaction mixture was reacted at 50° C. for 16 h. After the reaction was completed, direct chromatography separation (petroleum ether: ethyl acetate V / V=20:1) was performed to obtain compound 7 with a yield of 63%. 1 H NMR(400MHz,Chloroform-d)δ7.97–7.92(m,2H),7.58(d,J=8.4Hz,2H),5.71(s,1H),5.58(dd,J=10.0,4.4Hz,1 H),4.24(dd,J=6.6,3.4Hz,2H),3.89(s,3H),1.92(m,J=35.4,9.2,4.4Hz,2H),1.79–1.62(m,6H),1.24(s,9H). 13C NMR(101MHz,Chloroform-d)δ177.36,167.23,158.23,140.91,129.65,128.22,127.25,1 06.24,71.06,69.29,52.07,38.85,34.60,30.57,27.22,25.22,22.78.HRMS(ESI):Calcd 361.2010for C 21 H 28 O 5 [M+H] + Found:361.2009.

[0067] Example 8 Compound 8 Synthesis

[0068] Referring to the above-mentioned substrate synthesis method, the aldehyde is 3-furancarboxaldehyde, and the acyl chloride is trimethylacetyl chloride. The reaction is carried out to obtain the substrate eight. The NMR data are as follows:

[0069] 1 H NMR(400MHz,Chloroform-d)δ7.53(d,J=1.6Hz,1H),7.37(d,J=1.8Hz,1H),6.45–6.41(m,1H),6.35( d,J=2.2Hz,1H),3.64(t,J=6.4Hz,2H),2.26(td,J=6.9,2.0Hz,2H),1.60–1.44(m,7H),1.20(s,9H). 13 C NMR (101 MHz, CDCl 3 )δ177.56,143.53,141.30,123.66,109.56,86.35,76.63,62.87,58.73,38.85,32.27,28.21,27.08,25.01,18.80.HRMS(ESI):Calcd 315.1567for C 17 H 24 O 4

[0070] [M+Na] + Found:315.1565.

[0071] Under nitrogen conditions, tetrakis(triphenylphosphine)palladium (0.03mmol), substrate octadecene (0.3mmol), ligand L (dppf) (0.033mmol), arylboronic acid (0.03mmol), potassium pivalate (0.075mmol) were added to a 25mL Shrek tube in sequence. ，Isopropyl ether (4 mL) and tetrahydrofuran (2 mL) were mixed evenly at room temperature, and the reaction mixture was reacted at 50° C. for 16 h. After the reaction was completed, direct chromatography separation (petroleum ether: ethyl acetate V / V=10:1) was performed to obtain compound 8 with a yield of 65%. 1 H NMR (400MHz, Chloroform-d) δ7.59(s,1H),7.35(s,J=2.0Hz,1H),6.54(s,J=1.8Hz,1H),5.58(s,1H),5.52(dd,J=8.6,5. 4Hz,1H),4.24–4.15(m,2H),3.76–3.72(m,1H),1.90–1.84(m,2H),1.70(dtd,J=12.2,7.0,6.2,3.5Hz,6H),1.22(s,9H). 13 C NMR(101MHz,Chloroform-d)δ177.43,154.69,142.40,140.93,120.27,110.87,99.65,71.76, 69.18,68.10,38.86,33.76,30.28,27.19(d,J=6.1Hz),25.73,25.05,22.80.HRMS(ESI):Calcd

[0072] 293.1748for C 17 H 24 O 4 [M+H] + Found:293.1748.

[0073] Example 9 Compound 9 Synthesis

[0074] Referring to the above-mentioned substrate synthesis method, the aldehyde is 3-thiophenecarboxaldehyde, and the acyl chloride is trimethylacetyl chloride. The reaction is carried out to obtain the substrate nine. The NMR data are as follows:

[0075] 1 H NMR(400MHz,Chloroform-d)δ7.39(dt,J=3.1,1.1Hz,1H),7.28(dd,J=5.0,3.0Hz,1H),7.12(dd,J=5.0,1.3Hz,1H ),6.46(td,J=2.1,0.7Hz,1H),3.63(t,J=6.4Hz,2H),2.27(td,J=6.9,2.2Hz,2H),1.61–1.44(m,7H),1.20(s,9H). 13 C NMR (101 MHz, CDCl3 )δ177.47,138.99,126.67,126.29,123.82,86.97,77.12,62.83,61.71,38.88,32.27,28.22,27.10,25.02,18.84.HRMS(ESI):Calcd 331.1338for C 17 H 24 O 3 S[M+Na] + Found:331.1337.

[0076] Under nitrogen conditions, tetrakis(triphenylphosphine)palladium (0.03mmol), substrate nine (0.3mmol), ligand L is dppf (0.033mmol), arylboronic acid (0.03mmol), potassium pivalate (0.075mmol) were added to a 25mL Shrek tube in sequence. ， Isopropyl ether (4 mL) and tetrahydrofuran (2 mL) were mixed at room temperature, and the reaction mixture was reacted at 30° C. for 16 h. After the reaction was completed, direct chromatography separation (petroleum ether: ethyl acetate V / V = 100: 1) was performed to obtain compound 9 with a yield of 88%. 1 H NMR(400MHz,Chloroform-d)δ7.39–7.34(m,1H),7.27–7.20(m,2H),5.81(s,1H),5.58–5.50(m,1H),4.28–

[0077] 4.11(m,2H),1.96–1.87(m,2H),1.77–1.64(m,6H),1.23(s,9H). 13 C NMR(101MHz,Chloroform-d)δ177.39,154.51,136.44,128.59,124.57,122.04,1 03.76,71.90,69.39,38.85,33.74,30.21,27.23,25.20,22.85.HRMS(ESI):Calcd 309.1519for C 17 H 24 O 3 S[M+H] + Found:309.1515.

[0078] Example 10 Compound 10 Synthesis

[0079] Referring to the above-mentioned substrate synthesis method, the aldehyde is p-methoxypyridine carboxaldehyde, and the acyl chloride is trimethylacetyl chloride. The reaction is carried out to obtain the substrate ten. The NMR data are as follows:

[0080] 1 H NMR(400MHz,Chloroform-d)δ8.29(d,J=2.4Hz,1H),7.69(dd,J=8.6,2.5Hz,1H),6.74(d,J=8.6Hz,1H),6.36(t,J=2.2Hz,1H),3. 94(s,3H),3.64(t,J=6.4Hz,2H),2.27(td,J=6.9,2.0Hz,2H),1.64(s,1H),1.57(q,J=6.8Hz,4H),1.51–1.44(m,2H),1.19(s,9H). 13 C NMR (101 MHz, CDCl 3 )δ177.46,164.38,146.40,138.23,126.80,110.99,88.23,76.74,63.69,62.88, 53.75,38.89,32.30,28.22,27.09,25.06,18.88.HRMS(ESI):Calcd334.2013for C 19 H 27 NO 4 [M+H] + Found:334.2008.

[0081] Under nitrogen conditions, tetrakis(triphenylphosphine)palladium (0.03mmol), substrate ten (0.3mmol), ligand L is dppf (0.033mmol), arylboronic acid (0.03mmol), potassium pivalate (0.075mmol) were added to a 25mL Shrek tube in sequence. ， Isopropyl ether (4 mL) and tetrahydrofuran (2 mL) were mixed at room temperature, and the reaction mixture was reacted at 50° C. for 16 h. After the reaction was completed, direct chromatography separation (petroleum ether: ethyl acetate V / V = 100: 1) was performed to obtain compound 10 with a yield of 70%. 1 H NMR(400MHz,Chloroform-d)δ8.25(d,J=2.4Hz,1H),7.85(dd,J=8.7,2.4Hz,1H),6.68(d,J=8.6Hz,1H),5.61(s,1H),5.53(dd, J=9.4,4.7Hz,1H),4.15(m,J=6.0,3.8Hz,2H),3.92(s,3H),1.97–1.85(m,3H),1.70(m,J=11.0,7.5,3.4Hz,5H),1.23(s,9H).. 13C NMR(101MHz,Chloroform-d)δ177.44,162.31,155.34,146.54,138.55,125.33,110.38,1 04.50,71.71,69.15,53.52,38.86,33.91,30.16,27.22,25.26,22.79.HRMS(ESI):Calcd 334.2013forC 19 H 27 NO 4 [M+H] + Found:334.2011.

[0082] Example 11 Compound 11 Synthesis

[0083] Referring to the above-mentioned substrate synthesis method, the aldehyde is benzaldehyde, and the acyl chloride is isobutyryl chloride, and the reaction is carried out to obtain the substrate 11: The NMR data are as follows:

[0084] 1 H NMR(400MHz,Chloroform-d)δ7.52–7.48(m,2H),7.40–7.32(m,3H),6.44(t,J=2.1Hz,1H),3.63(t,J=6.4Hz,2H),2 .57(h,J=7.0Hz,1H),2.28(td,J=6.9,2.1Hz,2H),1.62–1.43(m,7H),1.19(d,J=7.0Hz,3H),1.15(d,J=7.0Hz,3H). 13 C NMR (101 MHz, CDCl 3 )δ176.19,137.88,128.72,128.63,127.57,88.01,77.24,65.91,62.83,34.07,32.23,28.20,25.02,18.92,18.89,18.87.HRMS(ESI):Calcd 289.1798for C 18 H 24 O 3 [M+H] + Found:289.1586.

[0085] Under nitrogen conditions, tetrakis(triphenylphosphine)palladium (0.03mmol), substrate 11 (0.3mmol), ligand L (dppf (0.033mmol), arylboronic acid (0.03mmol), isopropyl ether (4mL), tetrahydrofuran (2mL) were added to a 25mL Shrek tube in sequence and mixed evenly at room temperature, and the reaction mixture was reacted at 50°C for 16h. After the reaction was completed, compound 11 was obtained by direct chromatography separation (petroleum ether: ethyl acetate V / V = 100: 1) with a yield of 78%. 1 H NMR(400MHz,Chloroform-d)δ7.39–7.34(m,1H),7.27–7.20(m,2H),5.81(s,1H),5.5 8–5.50(m,1H),4.28–4.11(m,2H),1.96–1.87(m,2H),1.77–1.64(m,6H),1.23(s,9H). 13 C NMR(101MHz,Chloroform-d)δ177.39,154.51,136.44,128.59,124.57,122.04,1 03.76,71.90,69.39,38.85,33.74,30.21,27.23,25.20,22.85.HRMS(ESI):Calcd 298.1798for C 18 H 24 O 3 [M+H] + Found:298.1795.

[0086] Example 12 Compound 12 Synthesis

[0087] Referring to the above-mentioned substrate synthesis method, the aldehyde is benzaldehyde, and the acyl chloride is 3,3-dimethylbutyryl chloride. The reaction is carried out to obtain the substrate twelve: The NMR data are as follows:

[0088] 1 H NMR (400 MHz, CDCl 3 ): δ7.94(s,1H),7.75(d,J=7.3Hz,1H),7.63(d,J=7.8Hz,1H),7.38(t,J=7.5Hz,1H),5.44(d,J=5.6Hz,1H) ,3.63(t,J=6.4Hz,2H),2.74(br,OH,1H),2.44(td,J=6.8,1.8Hz,2H),1.96(p,J=6.6Hz,2H),1.34(s,12H). 13 C NMR (100 MHz, CDCl3 ): δ140.47,134.73,133.00,129.54,128.11,85.40,83.99,81.27,64.68,43.72,31.23,24.89,16.32.HRMS(ESI):Calcd 339.1930for C 20 H 28 O 3 [M+Na] + Found:339.1931.

[0089] Under nitrogen, tetrakis(triphenylphosphine)palladium (0.03mmol), substrate dodeca (0.3mmol), ligand L (dppf (0.033mmol), arylboronic acid (0.03mmol), isopropyl ether (4mL), tetrahydrofuran (2mL) were added to a 25mL Shrek tube in sequence, mixed evenly at room temperature, and the reaction mixture was reacted at 50°C for 16h. After the reaction was completed, compound 12 was obtained by direct chromatography separation (petroleum ether: ethyl acetate V / V = 100: 1) with a yield of 87%. 1 H NMR(400MHz,Chloroform-d)δ7.54–7.49(m,2H),7.34–7.26(m,2H),7.20–7.14(m,1H),5.87(s,1H),5 .56–5.47(m,1H),4.13–4.02(m,2H),2.25(s,2H),1.98–1.91(m,2H),1.70–1.60(m,6H),1.05(s,9H). 13 C NMR(101MHz,Chloroform-d)δ171.41,154.77,135.65,128.50(d,J=33.4Hz),126.48,111.39, 73.31,70.17,48.30,32.71,31.08,29.80,29.31,25.80,23.03.HRMS(ESI):Calcd317.2111for C 20 H 28 O 3 [M+H] + Found:317.2102.

[0090] Example 13 Compound 13 Synthesis

[0091] Synthesis was performed using the substrate 1 prepared in Example 1: under nitrogen conditions, tetrakis(triphenylphosphine)palladium (0.03mmol), substrate 1 (0.3mmol), ligand (0.033mmol), arylboronic acid (0.03mmol), isopropyl ether (4mL), and tetrahydrofuran (2mL) were added to a 25mL Shrek tube in sequence and mixed evenly at room temperature, and the reaction mixture was reacted at 100°C for 16h. After the reaction was completed, compound 13 was obtained by direct chromatography separation (cyclohexane) with a yield of 87%. 1 H NMR(400MHz,Chloroform-d)δ7.68(d,J=7.7Hz,2H),7.33(t,J=7.6Hz,2H),7.20(t,J=7.4Hz,1H),6.08(d,J=11.6H z,1H),5.79–5.68(m,2H),4.15–4.02(m,2H),2.58(m,J=7.4,7.0Hz,2H),1.81(m,J=5.6Hz,2H),1.74–1.66(m,2H). 13 C NMR (100 MHz, CDCl 3 ): δ155.03,136.11,131.14,129.17,128.41,128.39,126.42,116.04,71.03,27.06,26.67,25.02.HRMS(ESI):Calcd 200.2810forC 14 H 16 O[M+H] + Found:201.2883.

[0092] Example 14 Compound 14 Synthesis

[0093] Synthesis was performed using the substrate 2 prepared in Example 2: under nitrogen conditions, tetrakis(triphenylphosphine)palladium (0.03mmol), substrate 2 (0.3mmol), ligand L (dppf (0.033mmol), arylboronic acid (0.03mmol), isopropyl ether (4mL), and tetrahydrofuran (2mL) were added to a 25mL Shrek tube in sequence, mixed evenly at room temperature, and the reaction mixture was reacted at 100°C for 16h. After the reaction was completed, compound 14 was obtained by direct chromatography separation (cyclohexane) with a yield of 70%. 1H NMR(400MHz,Chloroform-d)δ8.16(d,J=2.1Hz,1H),7.15–7.05(m,2H),7.04–6.93(m,1H),6.08(d,J=11.7Hz,1 H),5.96(s,1H),5.82–5.68(m,1H),4.12–4.04(m,2H),2.56–2.49(m,2H),1.84–1.76(m,2H),1.74–1.63(m,2H). 13 C NMR(101MHz,Chloroform-d)δ160.98,158.52,156.22(d,J=2.1Hz),132.21,129.42(d,J=2.9Hz),128.78 ,127.56(d,J=8.6Hz),124.08(d,J=3.5Hz),115.12,114.90,106.06,105.99,71.11,27.50,26.98,24.73. 19 F NMR(376MHz,Chloroform-d)δ-117.65.HRMS(ESI):Calcd 219.1180for C 14 H 15 FO[M+H] + Found:219.1179.

[0094] Example 15 Compound 15 Synthesis

[0095] Synthesis was performed using the substrate three prepared in Example 3: under nitrogen conditions, tetrakis(triphenylphosphine)palladium (0.03mmol), substrate three (0.3mmol), ligand L (dppf (0.033mmol), arylboronic acid (0.03mmol), isopropyl ether (4mL), and tetrahydrofuran (2mL) were added to a 25mL Shrek tube in sequence, mixed evenly at room temperature, and the reaction mixture was reacted at 100°C for 16h. After the reaction was completed, compound 15 was obtained by direct chromatography separation (cyclohexane) with a yield of 76%. 1H NMR(400MHz,Chloroform-d)δ7.51(m,J=11.2,2.6,1.5Hz,1H),7.42–7.10(m,2H),6.97–6.71(m,1H),6.02(d,J=11.6Hz,1H),5 .76(dt,J=11.7,8.2Hz,1H),5.67(s,1H),4.22–3.93(m,2H),2.72–2.36(m,2H),1.80(m,J=6.3,4.6Hz,2H),1.73–1.64(m,2H). 13 C NMR (101MHz, Chloroform-d)δ1 13 C NMR(101MHz,Chloroform-d)δ163.06(d,J=243.3Hz),155.98,138.43(d,J=8.5Hz),132.54,129.61(d,J=8.6Hz),128.4 1,124.32(d,J=2.6Hz), 114.67(d,J=22.7Hz), 114.31(d,J=2.9Hz), 113.16(d,J=21.6Hz), 71.03, 27.52, 26.99, 24.67. 19 F NMR(376MHz,Chloroform-d)δ-113.87.HRMS(ESI):Calcd 219.1180for C 14 H 15 FO[M+H] + Found:219.118.

[0096] Example 16 Compound 16 Synthesis

[0097] Synthesis was performed using substrate 4 prepared in Example 4: under nitrogen conditions, tetrakis(triphenylphosphine)palladium (0.03mmol), substrate 4 (0.3mmol), ligand L (dppf (0.033mmol), arylboronic acid (0.03mmol), isopropyl ether (4mL), and tetrahydrofuran (2mL) were added to a 25mL Shrek tube in sequence, mixed evenly at room temperature, and the reaction mixture was reacted at 100°C for 16h. After the reaction was completed, compound 16 was obtained by direct chromatography separation (cyclohexane) with a yield of 92%. 1H NMR(400MHz,Chloroform-d)δ7.72–7.50(m,2H),7.32–7.13(m,2H),6.04(d,J=11.6Hz,1H),5.76(m,J=11.6,8.2H z,1H),5.68(s,1H),4.15–4.03(m,21H),2.55(m,J=8.1,5.8Hz,2H),1.81(m,J=5.7,3.8Hz,2H),1.74–1.67(m,2H). 13 C NMR (101 MHz, CDCl 3 )δ155.48,134.75,132.00,131.72,129.65,128.68,128.55,114.46,71.05,27.35,26.89,24.82.HRMS(ESI):Calcd235.0884 for C 14 H 15 ClO[M+H] + Found:235.0885.

[0098] Example 17 Compound 17 Synthesis

[0099] Synthesis was performed using the substrate five prepared in Example 5: under nitrogen conditions, tetrakis(triphenylphosphine)palladium (0.03mmol), substrate five (0.3mmol), ligand L (dppf (0.033mmol), arylboronic acid (0.03mmol), isopropyl ether (4mL), and tetrahydrofuran (2mL) were added sequentially into a 25mL Shrek tube, mixed evenly at room temperature, and the reaction mixture was reacted at 100°C for 16h. After the reaction was completed, compound 17 was obtained by direct chromatography separation (petroleum ether: ethyl acetate V / V = 20:1) with a yield of 65%. 1 H NMR(400MHz,Chloroform-d)δ7.72–7.68(m,2H),7.56–7.52(m,2H),6.01(dd,J=11.8,1.3Hz,1H),5.85(dt,J=11.8,7.9 Hz,1H),5.63(s,1H),4.15–4.11(m,2H),2.52–2.44(m,2H),1.81(td,J=6.3,4.7Hz,2H),1.69(m,J=9.3,6.1,3.0Hz,2H). 13 C NMR (101 MHz, CDCl 3)δ157.82,141.17,134.62,132.16,128.57,127.34,119.64,112.67,108.76,70.90,28.07,27.42,23.93.HRMS(ESI):Calcd 226.1227for C 15 H 15 NO[M+H] + Found:226.1221.

[0100] Example 18 Compound 18 Synthesis

[0101] Synthesis was performed using the substrate VI prepared in Example 6: under nitrogen conditions, tetrakis(triphenylphosphine)palladium (0.03mmol), substrate VI (0.3mmol), ligand L (dppf (0.033mmol), arylboronic acid (0.03mmol), isopropyl ether (4mL), and tetrahydrofuran (2mL) were added to a 25mL Shrek tube in sequence, mixed evenly at room temperature, and the reaction mixture was reacted at 100°C for 16h. After the reaction was completed, compound 18 was obtained by direct chromatography separation (petroleum ether: ethyl acetate V / V = 20:1) with a yield of 63%. 1 H NMR(400MHz,Chloroform-d)δ7.76–7.49(m,2H),6.85(d,J=8.9Hz,2H),6.04(d,J=11.4Hz,1H),5.70(s,1H),5.69– 5.59(m,1H),4.12–4.02(m,1H),3.81(s,3H),2.55(m,J=8.2,6.0Hz,2H),1.83–1.75(m,2H),1.69(q,J=6.2Hz,2H). 13 C NMR (101 MHz, CDCl 3 )δ158.28,153.62,129.91,129.76,129.62,128.97,116.07,113.92,71.12,55.35,26.90,26.59,25.43.HRMS(ESI):Calcd 231.1380for C 15 H 18 O 2 [M+H] + ;

[0102] Found:231.1375.

[0103] Example 19 Compound 19 Synthesis

[0104] Synthesis was performed using the substrate VII prepared in Example 7: under nitrogen conditions, tetrakis(triphenylphosphine)palladium (0.03mmol), substrate VII (0.3mmol), ligand L (dppf (0.033mmol), arylboronic acid (0.03mmol), isopropyl ether (4mL), and tetrahydrofuran (2mL) were added sequentially into a 25mL Shrek tube and mixed evenly at room temperature, and the reaction mixture was reacted at 100°C for 16h. After the reaction was completed, compound 19 was obtained by direct chromatography separation (petroleum ether: ethyl acetate V / V = 20:1) with a yield of 65%. 1 H NMR(400MHz,Chloroform-d)δ7.95(d,J=8.6Hz,2H),7.69(d,J=8.5Hz,2H),6.04(d,J=11.7Hz,1H),5.80(m,J=11.7,8.1 Hz,1H),5.71(s,1H),4.16–4.06(m,2H),3.90(s,3H),2.57–2.47(m,2H),1.80(m,J=6.0,3.5Hz,2H),1.75–1.64(m,2H). 13 C NMR(101MHz,Chloroform-d)δ167.22,157.02,141.09,133.36,129.78,128.26 ,128.14,127.44,114.28,71.05,52.08,27.65,27.14,24.42.HRMS(ESI):Calcd 259.1329for C 16 H 18 O 3 [M+H] + Found:259.1321.

[0105] Example 20 Compound 20 Synthesis

[0106] Synthesis was performed using the substrate VIII prepared in Example 8: under nitrogen conditions, tetrakis(triphenylphosphine)palladium (0.03mmol), substrate VIII (0.3mmol), ligand L (dppf (0.033mmol), arylboronic acid (0.03mmol), isopropyl ether (4mL), and tetrahydrofuran (2mL) were added to a 25mL Shrek tube in sequence, mixed evenly at room temperature, and the reaction mixture was reacted at 100°C for 16h. After the reaction was completed, compound 20 was obtained by direct chromatography separation (petroleum ether: ethyl acetate V / V = 20:1) with a yield of 62%. 1H NMR(400MHz,Chloroform-d)δ7.67(s,1H),7.36(d,J=1.8Hz,1H),6.63(d,J=1.8Hz,1H),6.03(d,J=11.6Hz,2H) ,5.65(q,J=7.1,5.9Hz,2H),4.11–4.02(m,2H),2.54(q,J=7.2Hz,2H),1.83–1.73(m,2H),1.68(d,J=6.3Hz,2H). 13 C NMR (100 MHz, CDCl 3 ): δ154.23,142.74,141.21,130.02,128.66,120.95,110.61,107.18,71.10,26.80,26.56,25.26.

[0107] Example 21 Compound 21 Synthesis

[0108] Synthesis was performed using the substrate 9 prepared in Example 9: under nitrogen conditions, tetrakis(triphenylphosphine)palladium (0.03mmol), substrate 9 (0.3mmol), ligand L (dppf (0.033mmol), arylboronic acid (0.03mmol), isopropyl ether (4mL), and tetrahydrofuran (2mL) were added to a 25mL Shrek tube in sequence, mixed evenly at room temperature, and the reaction mixture was reacted at 100°C for 16h. After the reaction was completed, compound 21 was obtained by direct chromatography separation (cyclohexane) with a yield of 70%. 1 H NMR (400 MHz, CDCl 3 ): δ7.46(dd,J=3.1,1.2Hz,1H),7.35(dd,J=5.1,1.2Hz,1H),7.24(dd,J=5.0,3.0Hz,1H),6.03(dd,J=11.5,1.1Hz,1H) ,5.84(s,1H),5.68(m,J=11.6,8.3Hz,1H),4.14–4.04(m,2H),2.58–2.50(m,2H),1.82–1.75(m,2H),1.72–1.65(m,2H). 13 C NMR (101 MHz, CDCl 3 )δ153.90,137.01,130.76,128.86,128.44,124.88,122.39,110.98,71.17,27.03,26.71,25.19.HRMS(ESI):Calcd 207.0838for C 12 H 14OS[M+H] + Found:207.0837.

[0109] Example 22 Compound 22 Synthesis

[0110] Synthesis was performed using the substrate ten prepared in Example 10: under nitrogen conditions, tetrakis(triphenylphosphine)palladium (0.03mmol), substrate ten (0.3mmol), ligand L (dppf (0.033mmol), arylboronic acid (0.03mmol), isopropyl ether (4mL), and tetrahydrofuran (2mL) were added to a 25mL Shrek tube in sequence, mixed evenly at room temperature, and the reaction mixture was reacted at 100°C for 16h. After the reaction was completed, compound 22 was obtained by direct chromatography separation (cyclohexane) with a yield of 78%. 1 H NMR(400MHz,Chloroform-d)δ8.31(t,J=2.0Hz,1H),8.01(m,J=8.8,2.0Hz,1H),6.69(d,J=8.6Hz,1H),6.02(d,J=11.6Hz,1H),5.75– 5.65(m,1H),5.63(s,1H),4.08–4.02(m,2H),3.93(s,3H),2.52(m,J=7.2Hz,2H),1.77(m,J=5.7Hz,2H),1.68(m,J=12.9,6.8Hz,2H). 13 C NMR(101MHz,Chloroform-d)δ162.48,154.78,146.70,138.25,131.22,128.63 ,125.81,112.02,110.63,71.11,53.54,27.23,26.77,24.94.HRMS(ESI):Calcd 236.1565forC 14 H 17 NO 2 [M+H] + Found:237.1683.

[0111] Example 23 Compound 23 Synthesis

[0112] Synthesis was performed using the substrate 11 prepared in Example 11: under nitrogen conditions, tetrakis(triphenylphosphine)palladium (0.03mmol), substrate 11 (0.3mmol), ligand L (dppf (0.033mmol), arylboronic acid (0.03mmol), isopropyl ether (4mL), and tetrahydrofuran (2mL) were added to a 25mL Shrek tube in sequence, mixed evenly at room temperature, and the reaction mixture was reacted at 100°C for 16h. After the reaction was completed, compound 23 was obtained by direct chromatography separation (cyclohexane) with a yield of 70%. 1 H NMR(400MHz,Chloroform-d)δ7.68(d,J=7.7Hz,2H),7.33(t,J=7.6Hz,2H),7.20(t,J=7.4Hz,1H),6.08(d,J=11.6H z,1H),5.79–5.68(m,2H),4.15–4.02(m,2H),2.58(m,J=7.4,7.0Hz,2H),1.81(m,J=5.6Hz,2H),1.74–1.66(m,2H). 13 C NMR (100 MHz, CDCl 3 ): δ155.03,136.11,131.14,129.17,128.41,128.39,126.42,116.04,71.03,27.06,26.67,25.02.HRMS(ESI):Calcd 200.2810for C 14 H 16 O[M+H] + Found:201.2883.

[0113] Example 24 Compound 24 Synthesis

[0114] Synthesis was performed using the substrate 12 prepared in Example 12: under nitrogen conditions, tetrakis(triphenylphosphine)palladium (0.03mmol), substrate 12 (0.3mmol), ligand L (dppf (0.033mmol), arylboronic acid (0.03mmol), isopropyl ether (4mL), and tetrahydrofuran (2mL) were added to a 25mL Shrek tube in sequence, mixed evenly at room temperature, and the reaction mixture was reacted at 100°C for 16h. After the reaction was completed, compound 24 was obtained by direct chromatography separation (cyclohexane) with a yield of 74%. 1H NMR(400MHz,Chloroform-d)δ7.68(d,J=7.7Hz,2H),7.33(t,J=7.6Hz,2H),7.20(t,J=7.4Hz,1H),6.08(d,J=11.6H z,1H),5.79–5.68(m,2H),4.15–4.02(m,2H),2.58(m,J=7.4,7.0Hz,2H),1.81(m,J=5.6Hz,2H),1.74–1.66(m,2H). 13 C NMR (100 MHz, CDCl 3 ): δ155.03,136.11,131.14,129.17,128.41,128.39,126.42,116.04,71.03,27.06,26.67,25.02.HRMS(ESI):Calcd 200.2810for C 14 H 16 O[M+H] + Found:201.2883.

[0115] Comparative Example 1

[0116] The method of Comparative Example 1 is the same as that of Example 1, except that no palladium catalyst is added and the yield of the target product is 0.

[0117] Comparative Example 2

[0118] Comparative Example 2 is the same as Example 1, except that ligand L is not added and the target product is compound 1 And the yield is 5%.

[0119] The above is only a preferred embodiment of the present invention, and is not intended to limit the present invention in any form. Although the present invention has been disclosed as above with a preferred embodiment, it is not intended to limit the present invention. The various palladium catalysts in the present invention can theoretically form cyclobutene palladium species from propargyl alcohol ester, thereby facilitating the smooth progress of the reaction; the modification of the substituent only affects the reaction to a certain extent, and does not play a decisive role in the occurrence of the reaction. It is not difficult for any technician familiar with this profession to understand that, without departing from the scope of the technical solution of the present invention, when changes or modifications can be made to obtain corresponding embodiments, for example, the substituents can be replaced, changed or modified within the scope of the present invention, and the method of the present invention can be realized. However, any modification, modification or equivalent and equivalent changes made to the above embodiments according to the present invention without departing from the purpose of the technical solution of the present invention still fall within the scope of the technical solution of the present invention.

Claims

1. A method for preparing cyclic ethers based on propargyl compounds, characterized in that: The method specifically comprises: in an organic solvent, using propargyl alcohol ester As raw materials, palladium as catalyst, arylboronic acid as additive, ligand L, and then react at 30-50 or 80-100°C for 10-20 hours to obtain Wherein, R is a heteroaryl, furan, or thiophene group containing N, O, or S, which is unsubstituted or substituted at any position on the aromatic ring by a C1-C20 alkyl group, a C1-C20 alkylcarbonyl group, a C1-C20 alkylnitro group, a C1-C20 alkylcyano group, or a C1-C20 alkylcyano group; The OPG is a C1-C20 alkyl carbonyl group; n is an integer from 1 to 7.

2. A method for preparing cyclic ethers based on a propargyl compound according to claim 1, characterized in that: The palladium is one or more of palladium acetate, palladium pivalate, tetrakis(triphenylphosphine)palladium, di(tri-tert-butylphosphine)palladium, tris(dicyclohexylphosphine)palladium dichloride, bis(tri-o-tolylphosphine)palladium dichloride, bis(methyldiphenylphosphine)palladium dichloride, bis(acetonitrile)palladium dichloride, bis(benzonitrile)palladium dichloride, bis(dibenzylideneacetone)palladium, and tris(dibenzylideneacetone)dipalladium.

3. A method for preparing cyclic ethers based on a propargyl compound according to claim 1, characterized in that: The ligand L includes a bidentate P ligand or a monodentate chiral P ligand.

4. A method for preparing cyclic ethers based on a propargyl compound according to claim 1, characterized in that: The organic solvent is at least one of toluene, dichloromethane, 1,2-dichloroethane, isopropyl ether, cyclopentyl methyl ether, ethylene glycol dimethyl ether, ethyl acetate, 1,4-dioxane or tetrahydrofuran.

5. A method for preparing cyclic ethers based on a propargyl compound according to claim 1, characterized in that: The molar ratio of the propargyl alcohol ester, palladium and ligand L is 1:0.1-0.3:0.1-0.

3.

6. The method for preparing cyclic ether based on a propargyl compound according to claim 1, characterized in that: The temperature is 30-50°C, the time is 10-20 hours, and the obtained product is 7. A method for preparing cyclic ethers based on propargyl compounds according to claim 1, characterized in that: The reaction temperature is 80-100°C, the reaction time is 10-20 hours, and the obtained product is 8. The method for preparing cyclic ether based on a propargyl compound according to claim 1, characterized in that: Propargyl alcohol ester The preparation method is: Step 1, to a 50 mL reaction bottle, add propargyl alcohol (5.0 mmol, 1.00 equiv), tert-butyldimethylsilyl chloride (10.0 mmol, 2.00 equiv), imidazole (10.0 mmol, 2.00 equiv), and dichloromethane (25 mL, 0.2 M) in sequence, react at 20 ° C for 5 hours, quench with saturated ammonium chloride solution, extract with dichloromethane, and separate by chromatography to obtain propargyl ether; Step 2, under nitrogen conditions, propargyl ether (4.8mmol, 1.00equiv) and tetrahydrofuran (17mL, 0.3M) were added to a 50mL reaction bottle in sequence, mixed evenly at 20°C, and n-butyl lithium was added dropwise in a 0°C environment. After reacting for 10 minutes, aldehyde (4.8mmol, 1.0equiv) was added dropwise, and then the reaction bottle was moved to 20°C for reaction for 1 hour, and then the reaction bottle was placed at 0°C, and acyl chloride (5.76mmol, 1.2equiv) was added dropwise, and then moved to 20°C for reaction for 2 hours, quenched with water, and then extracted with ethyl acetate, filtered with anhydrous sodium sulfate, and vacuum dried, tetrahydrofuran (25mL, 0.2M) was added, TABF solution (7.2mmol, 1.5equiv, 1MinTHF) was added dropwise at 0°C, and then placed at 20°C for reaction for 1 hour, and the reaction was quenched with saturated ammonium chloride solution, extracted with ethyl acetate, and separated by chromatography to obtain the target product propargyl alcohol ester.

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