Synthesis method of 1, 1-dialkyl substituted olefin

Abstract

The invention discloses a synthesis method of 1, 1-dialkyl substituted olefin, which comprises the following steps: taking terminal alkyne as an initial raw material, taking alkyl bromide as an alkyl source, adding a catalyst, a ligand, a hydrogen source, alkali and a solvent, and carrying out coupling reaction at specific temperature and reaction time under the protection of nitrogen to finally obtain the pharmaceutical and chemical intermediate 1, 1-dialkyl substituted olefin. The invention discloses a 1, 1-dialkyl substituted olefin compound. The method has the advantages that the raw materials are low in cost and easy to obtain, the reaction conditions are mild, the method can be implemented at room temperature, and the experimental operation is simple and convenient. In addition, the reaction also shows the characteristics of strong substrate adaptability, good functional group compatibility, excellent reaction selectivity, relatively high product yield, small influence on the environment and the like.

Description

Technical Field

[0001] The invention belongs to the technical field of pharmaceutical chemical intermediate synthesis, and specifically relates to a method for synthesizing 1,1-dialkyl substituted olefins. Background Art

[0002] As the basic skeleton of organic compounds, olefins are widely present in petrochemical products, natural products and synthetic molecules. Due to the presence of carbon-carbon double bonds, olefins can be modified to obtain new compounds, such as hydrosilylation, hydroboration, dihydroxylation, hydroboration and olefin metathesis. These reactions are of great value in organic synthetic chemistry and provide an effective way to construct complex molecular structures.

[0003] Elimination reaction is one of the common methods for synthesizing olefins. For example, olefins can be prepared from various alcohol compounds through elimination reaction. However, this method usually requires specific reaction conditions and catalysts, and the selectivity of the reaction may be affected by many factors, making it difficult to accurately control the generation of olefins with specific structures. Coupling reaction is also an important means of preparing olefins. For example, the coupling of Grignard reagents with olefins or halogenated aromatics can generate corresponding olefins (such as patent CN201610565022.1). However, such reactions often have some limitations, such as limited substrate application range, harsh reaction conditions, low yield, and the possibility of producing more by-products. For the synthesis of 1,1-dialkyl substituted olefins, traditional coupling reaction methods may not meet the requirements of high efficiency and high selectivity. In addition to elimination reactions and coupling reactions, there are some other methods that can be used for the synthesis of olefins, but these methods also have certain challenges in the synthesis of 1,1-dialkyl substituted olefins. For example, although some transition metal-catalyzed reactions can achieve the conversion of olefins, for the synthesis of 1,1-dialkyl substituted olefins, they may face problems such as low catalyst activity, poor selectivity, and complex reaction conditions.

[0004] 1,1-Dialkyl-substituted olefins are an important class of organic compounds that are commonly found in a large number of biologically active compounds and are also important intermediates in many target-oriented syntheses. Their special structure makes them exhibit unique reactivity and selectivity in chemical reactions, so they have important research value in the field of organic synthesis. Although a variety of olefin synthesis methods have been developed, the existing methods for the synthesis of 1,1-dialkyl-substituted olefins still have many shortcomings. Traditional synthesis methods often find it difficult to achieve highly selective synthesis of 1,1-dialkyl-substituted olefins, and are prone to produce other isomers as by-products, resulting in difficulties in separation and purification. In addition, the catalysts used in some methods are expensive and toxic, which does not meet the development requirements of green chemistry. At the same time, the harsh reaction conditions also limit the application of these methods in large-scale industrial production.

[0005] Therefore, developing a simple, efficient, highly selective and environmentally friendly method for the synthesis of 1,1-dialkyl substituted olefins has important theoretical significance and application value. Summary of the invention

[0006] The purpose of the present invention is to provide a method for synthesizing 1,1-dialkyl substituted olefins in view of the deficiencies of the prior art. The method is simple, efficient and has good research and application value.

[0007] To achieve the above object, the present invention adopts the following technical solution: Terminal alkyne 1, alkyl bromide 2, catalyst, ligand, hydrogen source, base, and solvent are mixed and subjected to coupling reaction in a nitrogen atmosphere to obtain 1,1-dialkyl substituted olefin 3; the synthetic route is as follows: Wherein, R is an alkyl group, an aryl group or a heteroaryl group; R 1 and R 2 Each of the following is independently selected from hydrogen, alkyl, cycloalkyl, phosphate or benzyl.

[0008] Preferably, the catalyst is a nickel salt, which is one of NiF2, NiI2, Ni(acac)2, NiCl2(PPh3)2, NiCl2(PCy3)2, Ni(dppf)Cl2, Ni(TMHD)2, Ni(COD)2, and Ni(OTf)2; more preferably, the catalyst is NiCl2(PCy3)2.

[0009] Preferably, the ligand is a nitrogen ligand or a phosphorus ligand, wherein the nitrogen ligand is one of 2,2'-bipyridine-4,4'-dicarboxylic acid, 2,2'-bipyridine-4,4'-dimethyl, 2,2'-bipyridine-4,4'-di-tert-butyl, 2,2'-bipyridine-4,4'-dimethoxy, 1,10-phenanthroline, and 2,9-dimethyl-1,10-phenanthroline; the phosphorus ligand is one of 1,2-di(diphenylphosphino)ethane and 1,2-di(dimethylphosphino)ethane; more preferably, the ligand is 2,2'-bipyridine-4,4'-di-tert-butyl.

[0010] Preferably, the hydrogen source is one of methyldiethoxysilane, diethylsilane, triethylsilane, diphenylsilane and triethoxysilane; more preferably, the hydrogen source is methyldiethoxysilane.

[0011] Preferably, the base is an organic base or an inorganic base, wherein the organic base is one of 4-dimethylaminopyridine, N,N-diisopropylethylamine, triethylamine, and DBU (1,8-diazabicyclo[5.4.0]undec-7-ene); the inorganic base is one of Na2CO3, Cs2CO3, K2CO3, Li2CO3, K2PO4, and K2HPO4•3H2O; more preferably, the base is K2HPO4•3H2O.

[0012] Preferably, the solvent is one of N-methylpyrrolidone, N,N-dimethylformamide, N,N-dimethylacetamide, tetrahydrofuran, toluene, dimethyl sulfoxide, and ethyl acetate; or two of the above solvents are selected and prepared into a mixed solvent in a certain proportion, with a volume ratio of 1 to 9:1 to 9; more preferably, the solvent is a mixed solvent of ethyl acetate and dimethyl sulfoxide, with a volume ratio of 7:3.

[0013] Preferably, the molar ratio of the terminal alkyne 1, the alkyl bromide 2, the catalyst, the ligand, the hydrogen source and the base is 1-3:1-3:0.05-0.2:0.05-0.3:1-10:1-10; more preferably, the molar ratio is 1.5:1:0.15:0.2:2:2.

[0014] Preferably, the reaction temperature is 0 to 100°C, more preferably 25°C.

[0015] Preferably, the reaction time is 1 to 24 hours, more preferably 10 hours.

[0016] The beneficial effects of the present invention are: The present invention uses cheap and readily available terminal alkynes and alkyl bromides as reaction raw materials, uses alkyl bromides as alkyl sources, and obtains a series of 1,1-dialkyl substituted olefin compounds with high selectivity and high yield through cross-coupling reaction under efficient and mild conditions of nickel catalysis; wherein, the terminal site of the terminal alkyne is easy to activate and selectively couple with the bromine atom, avoiding the reaction of other potential sites, and having good regional selectivity; in addition, no obvious by-product signal is detected, achieving high chemical selectivity. The new reaction involved in the present invention can be carried out at room temperature, has a simple preparation process, is environmentally friendly, has a wide range of applicable substrates, has strong functional group compatibility, and has good research and application value. DETAILED DESCRIPTION

[0017] The present invention is further described below.

[0018] As described above, the present invention discloses a method for synthesizing 1,1-dialkyl substituted olefins, comprising the following steps: adding a terminal alkyne 1, a bromoalkane 2, a catalyst, a ligand, a hydrogen source and a base in a molar ratio of 1 to 3: 1 to 3: 0.05 to 0.2: 0.05 to 0.3: 1 to 10: 1 to 10 to a reaction bottle, then adding a solvent, and performing a coupling reaction in a nitrogen atmosphere at 0 to 100° C. for 1 to 24 hours to obtain a 1,1-dialkyl substituted olefin 3; Wherein, the catalyst is selected from one of NiF2, NiI2, Ni(acac)2, NiCl2(PPh3)2, NiCl2(PCy3)2, Ni(dppf)Cl2, Ni(TMHD)2, Ni(COD)2, and Ni(OTf)2; The ligand is a nitrogen ligand or a phosphorus ligand; the nitrogen ligand is 2,2'-bipyridine-4,4'-dicarboxylic acid, 2,2'-bipyridine-4,4'-dimethyl, 2,2'-bipyridine-4,4'-di-tert-butyl, 2,2'-bipyridine-4,4'-dimethoxy, 1,10-phenanthroline, 2,9-dimethyl-1,10-phenanthroline; the phosphorus ligand is one of 1,2-bis(diphenylphosphino)ethane and 1,2-bis(dimethylphosphino)ethane; The hydrogen source is one of methyldiethoxysilane, diethylsilane, triethylsilane, diphenylsilane and triethoxysilane; The base is an organic base or an inorganic base; the organic base is one of 4-dimethylaminopyridine, N,N-diisopropylethylamine, triethylamine, and DBU; the inorganic base is one of Na2CO3, Cs2CO3, K2CO3, Li2CO3, K2PO4, and K2HPO4•3H2O; The solvent is one of N-methylpyrrolidone, N,N-dimethylformamide, N,N-dimethylacetamide, tetrahydrofuran, toluene, acetonitrile and dichloroethane; or two of the above solvents are selected and prepared into a mixed solvent in a certain ratio, with a volume ratio of 1 to 9:1 to 9; The present invention will be further described below in conjunction with specific examples. It should be understood that these examples are only used to illustrate the present invention and are not intended to limit the scope of the present invention.

[0019] Embodiment 1: Terminal alkyne 1a (17.4 mg, 0.10 mmol), α-bromophosphate ester 2a (50.3 mg, 0.15 mmol), bis(tricyclohexylphosphine)nickel chloride (10.3 mg, 0.015 mmol), 2,2'-bipyridine-4,4'-di-tert-butyl (5.4 mg, 0.02 mmol), methyldiethoxysilane (268.5 mg, 200 mol%), and potassium dihydrogen phosphate trihydrate (456.4 mg, 200 mol%) were added to a reaction flask, dissolved in a mixed solution of ethyl acetate and dimethyl sulfoxide (7:3, 1 mL), and reacted with stirring at 25 °C under nitrogen for 10 hours. After the reaction was completed, saturated sodium bicarbonate aqueous solution (10 g) was added to quench the reaction, and dichloromethane (10 g) was added. After sufficient stirring, the mixture was allowed to stand for stratification. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated to obtain a brown crude product. The crude product was purified by column method (eluent: ethyl acetate / petroleum ether = 1:20, v / v) to obtain a colorless liquid target product 3a (34.1 mg, 0.084 mmol, yield 84%). 1 H NMR (400 MHz, CDCl3) d 8.05-7.98 (m, 2H),7.57-7.48 (m, 1H), 7.40 (t, J = 7.7 Hz, 2H), 7.27-7.10 (m, 5H), 5.23 (d, J =4.9 Hz, 1H), 5.18 (d, J = 5.3 Hz, 1H), 4.54-4.39 (m, 2H), 4.14-3.95 (m, 4H), 2.80-2.69 (m, 1H), 2.67-2.60 (m, 2H), 2.60-2.46 (m, 2H), 2.27-2.13 (m, 1H), 2.12-1.94 (m, 1H), 1.26 (dd, J = 7.1, 7.1 Hz, 6H). 13 C NMR (101 MHz, CDCl3): d 166.6, 141.2, 140.2 (d, J = 8.8 Hz), 133.0, 130.3, 129.6, 128.5-128.4 (m),126.2, 115.8 (d, J = 11.0 Hz), 62.8 (d, J = 1.5 Hz), 62.3 (dd, J = 18.4, 7.1 Hz),43.9 (d, J= 136.2 Hz), 34.8 (d, J = 3.1 Hz), 33.5 (d, J = 15.2 Hz), 29.9 (d, J =3.5 Hz), 16.5 (dd, J = 5.9, 2.5 Hz). 31 P NMR (202 MHz, CDCl3): d 28.5. HRMS (ESI) m / z([M+H] + ) calcd for C 24 H 32 O5P: 431.1982. Found: 431.1981. Embodiment 2: Terminal alkyne 1b (20.4 mg, 0.10 mmol), α-bromophosphate ester 2a (50.3 mg, 0.15 mmol), bis(tricyclohexylphosphine)nickel chloride (10.3 mg, 0.015 mmol), 2,2'-bipyridine-4,4'-di-tert-butyl (5.4 mg, 0.02 mmol), methyldiethoxysilane (268.5 mg, 200 mol%), and potassium dihydrogen phosphate trihydrate (456.4 mg, 200 mol%) were added to a reaction flask, dissolved in a mixed solution of ethyl acetate and dimethyl sulfoxide (7:3, 1 mL), and reacted with stirring at 25 °C under nitrogen for 10 hours. After the reaction was completed, saturated sodium bicarbonate aqueous solution (10 g) was added to quench the reaction, and dichloromethane (10 g) was added. After sufficient stirring, the mixture was allowed to stand for stratification. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated to obtain a brown crude product. The crude product was purified by column method (eluent: ethyl acetate / petroleum ether = 1:20, v / v) to obtain a colorless liquid target product 3b (44.2 mg, 0.096 mmol, yield 96%). 1 H NMR (400 MHz, CDCl3): d 7.59-7.48 (m, 2H),7.26 (t, J = 7.9 Hz, 1H), 7.21-7.00 (m, 6H), 5.18 (d, J = 5.0 Hz, 1H), 5.13 (d, J= 5.4 Hz, 1H), 4.49 - 4.34(m, 2H), 4.09 - 3.91 (m, 4H), 3.76 (s, 3H), 2.76 - 2.64 (m,1H), 2.59 (t, 2H), 2.55 - 2.42 (m, 2H), 2.22 - 2.09 (m, 1H), 2.06 - 1.92 (m, 1H),1.22 (dd, J = 7.1, 7.1 Hz, 6H). 13 C NMR (126 MHz, CDCl3): d 166.5, 159.7, 141.2,140.2 (d, J = 8.6 Hz), 131.7, 129.5, 128.5 (d, J = 2.7 Hz), 126.2, 122.1, 119.6,115.8 (d, J = 10.9 Hz), 114.1, 63.0, 62.3 (dd, J = 21.3, 7.3 Hz), 55.5, 44.0 (d, J = 136.1 Hz), 34.9 (d, J = 3.2 Hz), 33.6 (d, J = 15.0 Hz), 29.9 (d, J = 3.6 Hz),16.6 (dd, J = 5.9, 3.2 Hz). 31 PNMR (162 MHz, CDCl3): d 28.4. HRMS (ESI) m / z ([M + H] + ) calcd for C 25 H 34 O6P: 461.2088. Found: 461.2089. Example 3: Terminal alkyne 1c (25.3 mg, 0.10 mmol), α-bromophosphate ester 2a (50.3 mg, 0.15 mmol), bis(tricyclohexylphosphine)nickel chloride (10.3 mg, 0.015 mmol), 2,2'-bipyridine-4,4'-di-tert-butyl (5.4 mg, 0.02 mmol), methyldiethoxysilane (268.5 mg, 200 mol%), and potassium dihydrogen phosphate trihydrate (456.4 mg, 200 mol%) were added to a reaction flask, dissolved in a mixed solution of ethyl acetate and dimethyl sulfoxide (7:3, 1 mL), and reacted with stirring at 25 °C under nitrogen for 10 hours. After the reaction was completed, saturated sodium bicarbonate aqueous solution (10 g) was added to quench the reaction, and dichloromethane (10 g) was added. After sufficient stirring, the mixture was allowed to stand for stratification. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated to obtain a brown crude product. The crude product was purified by column method (eluent: ethyl acetate / petroleum ether = 1:20, v / v) to obtain a colorless liquid target product 3c (31.0 mg, 0.061 mmol, yield 61%). 1 H NMR (400 MHz, CDCl3): δ 8.10 (t, J = 1.9 Hz,1H), 7.90 (d, J = 7.9 Hz, 1H), 7.65-7.57 (m, 1H), 7.25-7.17 (m, 3H), 7.14-7.06(m, 3H), 5.16 (d, J = 5.0 Hz, 1H), 5.13 (d, J = 5.4 Hz, 1H), 4.48-4.35 (m, 2H), 4.10-3.91 (m, 4H), 2.75-2.64 (m, 1H), 2.60 (t, 2H), 2.55-2.42 (m, 2H), 2.23-2.10 (m, 1H), 2.06-1.92 (m, 1H), 1.22 (dd, J = 6.9, 6.9 Hz, 6H). 13 C NMR (126 MHz,CDCl3): d 165.2, 141.2, 140.1 (d, J = 8.6 Hz), 136.0, 132.7, 132.3, 130.1, 128.5(d, J = 5.4 Hz), 128.2, 126.2, 122.6, 115.8 (d, J = 10.9 Hz), 63.3, 62.3 (dd,J =17.3, 7.3 Hz), 44.0 (d, J = 136.2 Hz), 34.7 (d, J = 3.2 Hz), 33.6 (d, J = 15.0 Hz),29.9 (d, J = 4.1 Hz), 16.6 (dd, J = 5.9, 2.7 Hz). 31 PNMR (162 MHz, CDCl3): d 28.3. HRMS (ESI) m / z ([M+H] + ) calcd for C 24 H 31 BrO5P: 509.1087. Found: 509.1087. Embodiment 4: Terminal alkyne 1d (18.8 mg, 0.10 mmol), α-bromophosphate ester 2a (50.3 mg, 0.15 mmol), bis(tricyclohexylphosphine)nickel chloride (10.3 mg, 0.015 mmol), 2,2'-bipyridine-4,4'-di-tert-butyl (5.4 mg, 0.02 mmol), methyldiethoxysilane (268.5 mg, 200 mol%), and potassium dihydrogen phosphate trihydrate (456.4 mg, 200 mol%) were added to a reaction flask, dissolved in a mixed solution of ethyl acetate and dimethyl sulfoxide (7:3, 1 mL), and reacted with stirring at 25 °C under nitrogen for 10 hours. After the reaction was completed, a saturated aqueous sodium bicarbonate solution (10 g) was added to quench the reaction, and dichloromethane (10 g) was added. After sufficient stirring, the mixture was allowed to stand for stratification. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated to obtain a brown crude product. The crude product was purified by column method (eluent: ethyl acetate / petroleum ether = 1:20, v / v) to obtain a colorless liquid target product 3d (36.4 mg, 0.082 mmol, yield 82%). 1 H NMR (500 MHz, CDCl3): d 7.87-7.80 (m, 2H),7.36-7.12 (m, 7H), 5.24 (d, J = 4.9 Hz, 1H), 5.20 (d, J= 5.3 Hz, 1H), 4.54 - 4.42(m, 2H), 4.15 - 3.99 (m, 4H), 2.81 - 2.72 (m, 1H), 2.65 (t, J = 6.8 Hz, 2H), 2.61 - 2.51 (m, 2H), 2.37 (s, 3H), 2.27 - 2.17 (m, 1H), 2.11 - 2.01 (m, 1H), 1.28 (td, J =9.5, 7.0 Hz, 6H). 13 C NMR (126 MHz, CDCl3): d 166.8, 141.2, 140.2 (d, J = 8.6 Hz),138.2, 133.8, 130.2 (d, J = 10.0 Hz), 128.5 (d, J = 2.3 Hz), 128.3, 126.8, 126.1,115.7 (d, J = 11.4 Hz), 62.8, 62.3 (dd, J = 24.1, 6.8 Hz), 44.0 (d, J = 135.9 Hz),34.9, 33.5 (d, J = 15.4 Hz), 29.9 (d, J = 3.6 Hz), 21.3, 16.5 (dd, J = 5.9, 2.7Hz). 31 PNMR (202 MHz, CDCl3): d 28.5. HRMS (ESI) m / z ([M + H] + ) calcd for C 25 H 34 O5P:445.2138. Found: 445.2139. Example 5: Terminal alkyne 1e (24.2 mg, 0.10 mmol), α-bromophosphate ester 2a (50.3 mg, 0.15 mmol), bis(tricyclohexylphosphine)nickel chloride (10.3 mg, 0.015 mmol), 2,2'-bipyridine-4,4'-di-tert-butyl (5.4 mg, 0.02 mmol), methyldiethoxysilane (268.5 mg, 200 mol%), and potassium dihydrogen phosphate trihydrate (456.4 mg, 200 mol%) were added to a reaction flask, dissolved in a mixed solution of ethyl acetate and dimethyl sulfoxide (7:3, 1 mL), and reacted with stirring at 25 °C under nitrogen for 10 hours. After the reaction was completed, saturated sodium bicarbonate aqueous solution (10 g) was added to quench the reaction, and dichloromethane (10 g) was added. After sufficient stirring, the mixture was allowed to stand for stratification. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated to obtain a brown crude product. The crude product was purified by column method (eluent: ethyl acetate / petroleum ether = 1:20, v / v) to obtain a colorless liquid target product 3e (29.9 mg, 0.060 mmol, yield 60%). 1 H NMR (500 MHz, CDCl3): d 8.14 (d, J = 8.2 Hz,2H), 7.68 (d, J = 8.2 Hz, 2H), 7.28-7.12 (m, 5H), 5.23 (d, J = 4.8 Hz, 1H), 5.20(d, J = 5.2 Hz, 1H), 4.56-4.47 (m, 2H), 4.12-4.02 (m, 4H), 2.79-2.72 (m, 1H), 2.67 (t, 2H), 2.61-2.51 (m, 2H), 2.28-2.17 (m, 1H), 2.11-2.00 (m, 1H), 1.28(td, 6H). 13 C NMR (126 MHz, CDCl3): d 165.4, 141.1, 140.1 (d, J = 9.1 Hz), 134.7,134.4, 133.6, 130.1, 126.2, 125.5 (q, J = 3.9 Hz), 124.8, 122.6, 115.8 (d, J =10.9 Hz), 63.4, 62.3 (dd, J = 13.9, 7.0 Hz), 44.0 (d, J= 136.3 Hz), 34.7, 33.6(d, J = 15.0 Hz), 29.8 (d, J = 3.6 Hz), 16.6 (dd, J = 5.9, 3.6 Hz). 31 PNMR (202 MHz,CDCl3): d 28.3. HRMS (ESI) m / z ([M+H] + ) calcd for C 25 H 31 F3O5P: 499.1856. Found: 499.1856. Embodiment 6: Terminal alkyne 1f (11.6 mg, 0.10 mmol), α-bromophosphate ester 2a (50.3 mg, 0.15 mmol), bis(tricyclohexylphosphine)nickel chloride (10.3 mg, 0.015 mmol), 2,2'-bipyridine-4,4'-di-tert-butyl (5.4 mg, 0.02 mmol), methyldiethoxysilane (268.5 mg, 200 mol%), and potassium dihydrogen phosphate trihydrate (456.4 mg, 200 mol%) were added to a reaction flask, dissolved in a mixed solution of ethyl acetate and dimethyl sulfoxide (7:3, 1 mL), and reacted with stirring at 25 °C under nitrogen for 10 hours. After the reaction was completed, saturated aqueous sodium bicarbonate solution (10 g) was added to quench the reaction, and dichloromethane (10 g) was added. After sufficient stirring, the mixture was allowed to stand for stratification. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated to obtain a brown crude product. The crude product was purified by column method (eluent: ethyl acetate / petroleum ether = 1:20, v / v) to obtain a colorless liquid target product 3f (26.0 mg, 0.070 mmol, yield 70%). 1 H NMR (400 MHz, CDCl3): d 7.25-7.11 (m, 5H),5.10-5.03 (m, 2H), 4.10-3.92 (m, 4H), 3.52 (t, J = 6.6 Hz, 2H), 2.76-2.64 (m,1H), 2.54-2.37 (m, 2H), 2.23-2.08 (m, 3H), 2.07-1.91 (m, 1H), 1.85-1.70 (m,1H), 1.61-1.56 (m, 1H), 1.31-1.19 (m, 8H). 13 C NMR(126 MHz, CDCl3): d 143.6 (d, J =8.6 Hz), 141.4, 128.5 (d, J = 5.9 Hz), 126.1, 113.7 (d, J = 10.4 Hz), 62.2 (dd, J =19.8, 7.0 Hz), 43.9 (d, J = 135.8 Hz), 35.3 (d, J = 3.2 Hz), 33.6 (d, J = 15.0 Hz),32.3, 30.2 (d, J = 3.6 Hz), 24.7, 16.6-16.4 (m). 31 PNMR (202 MHz, CDCl3): d 28.9. HRMS (ESI) m / z ([M+H] + ) calcd for C 19 H 31 ClO3P: 373.1694. Found: 373.1691. Embodiment 7: 1 g (13.3 mg, 0.10 mmol) of terminal alkyne, α-bromophosphate 2a (50.3 mg, 0.15 mmol), bis(tricyclohexylphosphine)nickel chloride (10.3 mg, 0.015 mmol), 2,2'-bipyridine-4,4'-di-tert-butyl (5.4 mg, 0.02 mmol), methyldiethoxysilane (268.5 mg, 200 mol%), and dipotassium hydrogen phosphate trihydrate (456.4 mg, 200 mol%) were added to a reaction flask, dissolved in a mixed solution of ethyl acetate and dimethyl sulfoxide (7:3, 1 mL), and reacted with stirring at 25 °C under nitrogen for 10 hours. After the reaction was completed, a saturated aqueous sodium bicarbonate solution (10 g) was added to quench the reaction, and dichloromethane (10 g) was added. After sufficient stirring, the mixture was allowed to stand for stratification. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated to obtain a brown crude product. The crude product was purified by column method (eluent: ethyl acetate / petroleum ether = 1:20, v / v) to obtain 3 g (22.1 mg, 0.057 mmol, yield 57%) of the target colorless liquid product. 1 H NMR (400 MHz, CDCl3): d7.28 - 7.12 (m, 5H), 5.20 - 5.13 (m, 2H), 4.11 - 3.96 (m, 4H), 3.55 - 3.38 (m, 2H), 2.81 - 2.60 (m, 3H), 2.56 - 2.39 (m, 2H), 2.23 - 2.12 (m, 1H), 2.04 - 1.95 (m, 1H), 1.27 (td, J J = 7.1, 5.9 Hz, 6H). 13 C NMR (126 MHz, CDCl3): d 141.2 - 141.0 (m), 128.6, 126.2, 116.0 (d, J J = 10.9 Hz), 62.3 (dd, J J = 12.3, 6.8 Hz), 44.2, 43.1, 39.1 (d, J J = 3.2 Hz), 33.5 (d, J J = 15.0 Hz), 30.3, 29.9 (d, J J = 3.6 Hz), 16.6 (dd, J J = 6.1, 3.0 Hz). 31 PNMR (202MHz, CDCl3): d 28.3. HRMS (ESI) m / z ([M + H] + ) calcd for C 17 H 27 BrO3P: 389.0876. Found: 389.0877. Example 8: Terminal alkyne 1h (18.8 mg, 0.10 mmol), α-bromophosphate 2a (50.3 mg, 0.15 mmol), bis(tricyclohexylphosphine)nickel chloride (10.3 mg, 0.015 mmol), 2,2'-bipyridine-4,4'-di-tert-butyl (5.4 mg, 0.02 mmol), methyldiethoxysilane (268.5 mg, 200 mol%), and potassium dihydrogen phosphate trihydrate (456.4 mg, 200 mol%) were added to a reaction flask, dissolved in a mixed solution of ethyl acetate and dimethyl sulfoxide (7:3, 1 mL), and reacted with stirring at 25 °C under nitrogen for 10 hours. After the reaction was completed, a saturated aqueous sodium bicarbonate solution (10 g) was added to quench the reaction, and dichloromethane (10 g) was added. After sufficient stirring, the mixture was allowed to stand for stratification. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated to obtain a brown crude product. The crude product was purified by column method (eluent: ethyl acetate / petroleum ether = 1:20, v / v) to obtain a colorless liquid target product 3h (27.1 mg, 0.061 mmol, yield 61%). 1 H NMR (400 MHz, CDCl3): d 7.92-7.85 (m, 1H),7.40-7.08 (m, 8H), 5.22 (d, J = 5.0 Hz, 1H), 5.18 (d, J = 5.3 Hz, 1H), 4.51-4.37(m, 2H), 4.13-3.95 (m, 4H), 2.79-2.68 (m, 1H), 2.63 (t, J = 8.0 Hz, 2H), 2.58(s, 3H), 2.56-2.47 (m, 2H), 2.26-2.13 (m, 1H), 2.11-1.96 (m, 1H), 1.27-1.23(m, 6H). 13 C NMR (101 MHz, CDCl3): d 167.6, 141.2, 140.3, 132.1, 131.8, 130.7,128.5 (d, J = 1.8 Hz), 126.2, 125.8, 115.7 (d, J = 11.3 Hz), 62.6 (d, J = 1.8 Hz),62.3 (dd, J = 17.6, 7.1 Hz), 44.0 (d, J = 136.2 Hz), 34.9 (d, J= 3.3 Hz), 33.6 (d, J = 15.3 Hz), 29.9 (d, J = 3.6 Hz), 21.9, 16.6 (dd, J = 6.0, 2.7 Hz). 31 PNMR (202MHz, CDCl3): d 28.4. HRMS (ESI) m / z ([M+H] + ) calcd for C 25 H 34 O5P: 445.2138. Found: 445.2139. Embodiment 9: Terminal alkyne 1i (24.2 mg, 0.10 mmol), α-bromophosphate ester 2a (50.3 mg, 0.15 mmol), bis(tricyclohexylphosphine)nickel chloride (10.3 mg, 0.015 mmol), 2,2'-bipyridine-4,4'-di-tert-butyl (5.4 mg, 0.02 mmol), methyldiethoxysilane (268.5 mg, 200 mol%), and potassium dihydrogen phosphate trihydrate (456.4 mg, 200 mol%) were added to a reaction flask, dissolved in a mixed solution of ethyl acetate and dimethyl sulfoxide (7:3, 1 mL), and reacted with stirring at 25 °C under nitrogen for 10 hours. After the reaction was completed, saturated aqueous sodium bicarbonate solution (10 g) was added to quench the reaction, and dichloromethane (10 g) was added. After sufficient stirring, the mixture was allowed to stand for stratification. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated to obtain a brown crude product. The crude product was purified by column method (eluent: ethyl acetate / petroleum ether = 1:20, v / v) to obtain a colorless liquid target product 3i (27.4 mg, 0.055 mmol, yield 55%). 1 H NMR (400 MHz, CDCl3): d 7.84-7.72 (m, 2H),7.66-7.56 (m, 2H), 7.32-7.11 (m, 5H), 5.21 (dd, J = 7.9, 5.0 Hz, 2H), 4.57-4.47(m, 2H), 4.15-3.99 (m, 4H), 2.79-2.70 (m, 1H), 2.65 (t, 2H), 2.60-2.49 (m,2H), 2.28-2.15 (m, 1H), 2.11-1.99 (m, 1H), 1.31-1.26 (m, 6H). 13 C NMR (101 MHz, CDCl3): d 166.9, 141.2, 139.9 (d, J J = 9.1 Hz), 131.9, 131.3, 130.3, 128.5 (d, J J = 1.8 Hz), 126.9 - 126.7 (m), 126.2, 115.8 (d, J J = 10.9 Hz), 64.0 (d, J J = 1.8 Hz), 62.3 (dd, J J = 17.6, 7.1 Hz), 44.1 (d, J J = 136.2 Hz), 34.4 (d, J J = 3.3 Hz), 33.5 (d, J J = 15.3 Hz), 29.9 (d, J J = 3.6 Hz), 16.5 (dd, J J = 6.0, 3.8 Hz). 31 PNMR (202 MHz, CDCl3): d 28.4. HRMS (ESI) m / z ([M + H] + ) calcd for C 25 H 31 F3O5P: 499.1856. Found: 499.1856. Example 10: Terminal alkyne 1j (18.0 mg, 0.10 mmol), α-bromophosphate ester 2a (50.3 mg, 0.15 mmol), bis(tricyclohexylphosphine)nickel chloride (10.3 mg, 0.015 mmol), 2,2'-bipyridine-4,4'-di-tert-butyl (5.4 mg, 0.02 mmol), methyldiethoxysilane (268.5 mg, 200 mol%), and potassium dihydrogen phosphate trihydrate (456.4 mg, 200 mol%) were added to a reaction flask, dissolved in a mixed solution of ethyl acetate and dimethyl sulfoxide (7:3, 1 mL), and reacted with stirring at 25 °C under nitrogen for 10 hours. After the reaction was completed, saturated aqueous sodium bicarbonate solution (10 g) was added to quench the reaction, and dichloromethane (10 g) was added. After sufficient stirring, the mixture was allowed to stand for stratification. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated to obtain a brown crude product. The crude product was purified by column method (eluent: ethyl acetate / petroleum ether = 1:20, v / v) to obtain a colorless liquid target product 3j (27.0 mg, 0.062 mmol, yield 62%). 1 H NMR (400 MHz, CDCl3): d 7.25-7.10 (m, 5H),5.12 (d, J = 5.1 Hz, 2H), 4.19 (t, J = 7.1 Hz, 2H), 4.07-3.98 (m, 4H), 2.78-2.65(m, 1H), 2.55-2.39 (m, 4H), 2.28-2.20 (m, 1H), 2.19-2.10 (m, 1H), 2.04-1.95(m, 1H), 1.91-1.80 (m, 2H), 1.75-1.65 (m, 2H), 1.64-1.54 (m, 1H), 1.47-1.34(m, 3H), 1.28-1.21 (m, 8H). 13 C NMR (126 MHz, CDCl3): d 176.1, 141.3, 140.2 (d, J =9.1 Hz), 128.5 (d, J = 2.7 Hz), 126.1, 115.5 (d, J = 10.9 Hz), 62.3 (d, J = 6.8Hz), 62.2-61.9 (m), 44.0 (d, J = 136.2 Hz), 43.3, 34.8, 33.5 (d, J= 15.0 Hz),29.9 (d, J = 3.6 Hz), 29.1, 25.8, 25.5, 16.5 (dd, J = 5.9, 2.7 Hz). 31 PNMR (202 MHz,CDCl3): d 28.5. HRMS (ESI) m / z ([M+H] + ) calcd for C 24 H 38 O5P: 437.2451. Found: 437.2451. Embodiment 11: Terminal alkyne 1k (13.0 mg, 0.10 mmol), α-bromophosphate 2a (50.3 mg, 0.15 mmol), bis(tricyclohexylphosphine)nickel chloride (10.3 mg, 0.015 mmol), 2,2'-bipyridine-4,4'-di-tert-butyl (5.4 mg, 0.02 mmol), methyldiethoxysilane (268.5 mg, 200 mol%), and potassium dihydrogen phosphate trihydrate (456.4 mg, 200 mol%) were added to a reaction flask, dissolved in a mixed solution of ethyl acetate and dimethyl sulfoxide (7:3, 1 mL), and reacted with stirring at 25 °C under nitrogen for 10 hours. After the reaction was completed, saturated aqueous sodium bicarbonate solution (10 g) was added to quench the reaction, and dichloromethane (10 g) was added. After sufficient stirring, the mixture was allowed to stand for stratification. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated to obtain a brown crude product. The crude product was purified by column method (eluent: ethyl acetate / petroleum ether = 1:20, v / v) to obtain a colorless liquid target product 3k (23.9 mg, 0.062 mmol, yield 62%). 1 H NMR (500 MHz, CDCl3): d 7.35-7.18 (m, 10H),5.23 (d, J = 4.9 Hz, 1H), 5.18 (d, J = 5.3 Hz, 1H), 4.19-4.00 (m, 4H), 2.92-2.72(m, 3H), 2.62-2.48 (m, 4H), 2.30-2.19 (m, 1H), 2.14-2.02 (m, 1H), 1.32 (td, J =9.9, 7.1 Hz, 6H). 13 C NMR (126 MHz, CDCl3): d143.8 (d, J = 8.6 Hz), 141.9, 141.4,128.6, 128.5-128.4 (m), 126.1, 126.0, 113.8 (d, J = 10.9 Hz), 62.2 (dd, J = 32.5,7.0 Hz), 44.2 (d, J = 135.7 Hz), 37.7 (d, J = 3.6 Hz), 34.0, 33.7 (d, J = 15.4 Hz),30.2 (d, J = 3.6 Hz), 16.6 (dd, J = 6.1, 2.5 Hz). 31 PNMR (162 MHz, CDCl3): d 29.0. HRMS (ESI) m / z ([M+H] + ) calcd for C 23 H 32 O3P: 387.2084. Found: 387.2085. Embodiment 12: Terminal alkyne 1l (13.8 mg, 0.10 mmol), α-bromophosphate ester 2a (50.3 mg, 0.15 mmol), bis(tricyclohexylphosphine)nickel chloride (10.3 mg, 0.015 mmol), 2,2'-bipyridine-4,4'-di-tert-butyl (5.4 mg, 0.02 mmol), methyldiethoxysilane (268.5 mg, 200 mol%), and potassium dihydrogen phosphate trihydrate (456.4 mg, 200 mol%) were added to a reaction flask, dissolved in a mixed solution of ethyl acetate and dimethyl sulfoxide (7:3, 1 mL M), and reacted with stirring at 25 °C under nitrogen for 10 h. After the reaction was completed, saturated sodium bicarbonate aqueous solution (10 g) was added to quench the reaction, and dichloromethane (10 g) was added. After sufficient stirring, the mixture was allowed to stand for stratification. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated to obtain a brown crude product. The crude product was purified by column method (eluent: ethyl acetate / petroleum ether = 1:20, v / v) to obtain a colorless liquid target product 3l (24.0 mg, 0.061 mmol, yield 61%). 1 H NMR (400 MHz, CDCl3): d 7.27-7.11 (m, 5H),5.12 (d,J = 5.0 Hz, 2H), 4.20 (t, J = 6.8 Hz, 2H), 4.11 - 3.93 (m, 4H), 2.77 - 2.65(m, 1H), 2.55 - 2.41 (m, 4H), 2.22 - 2.09 (m, 1H), 2.06 - 1.91 (m, 1H), 1.60 - 1.49(m, 1H), 1.27 - 1.21 (m, 6H), 0.99 - 0.89 (m, 2H), 0.83 - 0.77 (m, 2H). 13 C NMR (126MHz, CDCl3): d 174.9, 141.3, 140.2 (d, J = 8.6 Hz), 128.5, 126.2, 115.6 (d, J =11.4 Hz), 62.5 - 62.1 (m), 44.0 (d, J = 136.1 Hz), 34.8, 33.5 (d, J = 15.0 Hz),30.0 (d, J = 3.6 Hz), 16.6 (dd, J = 5.7, 2.5 Hz), 13.0, 8.5. 31 PNMR (202 MHz,CDCl3): d 28.4. HRMS (ESI) m / z ([M + H] + ) calcd for C 21 H 32 O5P: 395.1982. Found:395.1981. Example 13: Terminal alkyne 1m (18.0 mg, 0.10 mmol), α-bromophosphate ester 2a (50.3 mg, 0.15 mmol), bis(tricyclohexylphosphine)nickel chloride (10.3 mg, 0.015 mmol), 2,2'-bipyridine-4,4'-di-tert-butyl (5.4 mg, 0.02 mmol), methyldiethoxysilane (268.5 mg, 200 mol%), and potassium dihydrogen phosphate trihydrate (456.4 mg, 200 mol%) were added to a reaction flask, dissolved in a mixed solution of ethyl acetate and dimethyl sulfoxide (7:3, 1 mL), and reacted with stirring at 25 °C under nitrogen for 10 hours. After the reaction was completed, a saturated aqueous sodium bicarbonate solution (10 g) was added to quench the reaction, and dichloromethane (10 g) was added. After sufficient stirring, the mixture was allowed to stand for stratification. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated to obtain a brown crude product. The crude product was purified by column method (eluent: ethyl acetate / petroleum ether = 1:20, v / v) to obtain a colorless liquid target product 3m (34.0 mg, 0.078 mmol, yield 78%). 1 H NMR (500 MHz, CDCl3): d 7.77 (dd, J = 3.8, 1.3Hz, 1H), 7.52 (dd, J = 4.9, 1.4 Hz, 1H), 7.25-7.11 (m, 5H), 7.09-7.03 (m, 1H),5.21 (d, J = 4.9 Hz, 1H), 5.17 (d, J = 5.3 Hz, 1H), 4.50-4.37 (m, 2H), 4.13-3.97(m, 4H), 2.80-2.70 (m, 1H), 2.63-2.59 (m, 2H), 2.58-2.49 (m, 2H), 2.25-2.14(m, 1H), 2.10-1.97 (m, 1H), 1.30-1.24 (m, 6H). 13 C NMR (126 MHz, CDCl3): d 162.2,141.3, 140.0 (d, J = 8.6 Hz), 133.9, 133.5, 132.5, 128.5, 127.8, 126.1, 115.8(d, J = 11.4 Hz), 63.0, 62.2 (dd, J = 22.5, 7.0 Hz), 43.9 (d, J= 136.0 Hz), 34.9(d, J = 3.2 Hz), 33.5 (d, J = 15.0 Hz), 29.9 (d, J = 3.6 Hz), 16.5 (dd, J = 5.9, 2.3Hz). 31 PNMR (162 MHz, CDCl3): d 28.4. HRMS (ESI) m / z ([M+H] + ) calcd for C 22 H 30 O5PS:437.1546. Found: 437.1546. Embodiment 14: Terminal alkyne 1n (10.8 mg, 0.10 mmol), α-bromophosphate ester 2a (50.3 mg, 0.15 mmol), bis(tricyclohexylphosphine)nickel chloride (10.3 mg, 0.015 mmol), 2,2'-bipyridine-4,4'-di-tert-butyl (5.4 mg, 0.02 mmol), methyldiethoxysilane (268.5 mg, 200 mol%), and potassium dihydrogen phosphate trihydrate (456.4 mg, 200 mol%) were added to a reaction flask, dissolved in a mixed solution of ethyl acetate and dimethyl sulfoxide (7:3, 1 mL), and reacted with stirring at 25 °C under nitrogen for 10 hours. After the reaction was completed, saturated aqueous sodium bicarbonate solution (10 g) was added to quench the reaction, and dichloromethane (10 g) was added. After sufficient stirring, the mixture was allowed to stand for stratification. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated to obtain a brown crude product. The crude product was purified by column method (eluent: ethyl acetate / petroleum ether = 1:20, v / v) to obtain a colorless liquid target product 3n (15.7 mg, 0.043 mmol, yield 43%). 1 H NMR (400 MHz, CDCl3): d 7.3-7.2 (m, 6H), 7.2(d, J = 7.6 Hz, 2H), 5.8 (d, J = 5.8 Hz, 1H), 5.5 (d, J = 5.4 Hz, 1H), 4.1-4.0 (m,4H), 3.1 (ddd, J= 23.6, 10.9, 4.1 Hz, 1H), 2.91 - 2.79 (m, 1H), 2.7 - 2.6 (m, 1H), 2.47 - 2.33 (m, 1H), 2.3 - 2.2 (m, 1H), 1.3 - 1.2 (m, 6H). 13 C NMR (126 MHz, CDCl3): d 143.3 (d, J = 5.2 Hz), 141.3, 138.4 (d, J = 8.1 Hz), 128.7, 128.5, 126.5, 126.1, 125.7, 121.4, 115.4 (d, J = 9.4 Hz), 62.8 (d, J = 7.2 Hz), 62.0 (d, J = 7.2 Hz), 42.2 (d, J = 137.5 Hz), 33.4 (d, J = 15.1 Hz), 31.5 (d, J = 3.2 Hz), 16.5 (t, J = 5.6Hz). 31 PNMR (202 MHz, CDCl3): d 28.7. HRMS (ESI) m / z ([M + H] + ) calcd for C 19 H 26 O3PS: 365.1335. Found: 365.1336. Example 15: Terminal alkyne 1o (19.7 mg, 0.10 mmol), α-bromophosphate 2a (50.3 mg, 0.15 mmol), bis(tricyclohexylphosphine)nickel chloride (10.3 mg, 0.015 mmol), 2,2'-bipyridine-4,4'-di-tert-butyl (5.4 mg, 0.02 mmol), methyldiethoxysilane (268.5 mg, 200 mol%), and potassium dihydrogen phosphate trihydrate (456.4 mg, 200 mol%) were added to a reaction flask, dissolved in a mixed solution of ethyl acetate and dimethyl sulfoxide (7:3, 1 mL), and reacted with stirring at 25 °C under nitrogen for 10 hours. After the reaction was completed, saturated aqueous sodium bicarbonate solution (10 g) was added to quench the reaction, and dichloromethane (10 g) was added. After sufficient stirring, the mixture was allowed to stand for stratification. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated to obtain a brown crude product. The crude product was purified by column method (eluent: ethyl acetate / petroleum ether = 1:20, v / v) to obtain a colorless liquid target product 3o (26.3 mg, 0.084 mmol, yield 84%). 1 H NMR (500 MHz, CDCl3): d 7.49-7.44 (m, 1H),7.28-7.21 (m, 2H), 7.19-6.95 (m, 5H), 6.91 (d, J = 7.1 Hz, 1H), 6.46 (d, J = 3.1Hz, 1H), 5.08 (dd, J = 5.1, 2.5 Hz, 2H), 4.34 (t, J = 7.3 Hz, 2H), 4.07-3.96 (m,4H), 2.71 (s, 3H), 2.70-2.65 (m, 1H), 2.54-2.39 (m, 2H), 2.21-2.16 (m, 3H), 2.03-1.88 (m, 3H), 1.34-1.21 (m, 6H). 13 C NMR (126 MHz, CDCl3): d 143.2 (d, J = 8.6Hz), 141.2, 134.6, 129.9, 129.5, 128.5, 126.2, 124.6, 120.7, 119.6, 119.3,113.9 (d, J = 10.9 Hz), 101.6, 62.2 (dd, J = 9.8, 7.0 Hz), 48.6, 44.1 (d, J= 136.0Hz), 33.6 (d, J = 15.0 Hz), 33.0 (d, J = 3.2 Hz), 30.6, 30.1 (d, J = 4.1 Hz), 20.1,16.5 (t, J = 5.2 Hz). 31 PNMR (202 MHz, CDCl3): d 28.6. HRMS (ESI) m / z ([M+H] + ) calcdfor C 27 H 37 NO3P: 454.2506. Found: 454.2506. Embodiment 16: Terminal alkyne 1p (19.4 mg, 0.10 mmol), α-bromophosphate ester 2a (50.3 mg, 0.15 mmol), bis(tricyclohexylphosphine)nickel chloride (10.3 mg, 0.015 mmol), 2,2'-bipyridine-4,4'-di-tert-butyl (5.4 mg, 0.02 mmol), methyldiethoxysilane (268.5 mg, 200 mol%), and potassium dihydrogen phosphate trihydrate (456.4 mg, 200 mol%) were added to a reaction flask, dissolved in a mixed solution of ethyl acetate and dimethyl sulfoxide (7:3, 1 mL), and reacted with stirring at 25 °C under nitrogen for 10 hours. After the reaction was completed, a saturated aqueous sodium bicarbonate solution (10 g) was added to quench the reaction, and dichloromethane (10 g) was added. After sufficient stirring, the mixture was allowed to stand for stratification. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated to obtain a brown crude product. The crude product was purified by column method (eluent: ethyl acetate / petroleum ether = 1:20, v / v) to obtain a colorless liquid target product 3p (21.6 mg, 0.048 mmol, yield 48%). 1 H NMR (400 MHz, CDCl3): d 7.3-7.1 (m, 6H), 7.0-6.9 (m, 2H), 5.1 (t, J = 4.8 Hz, 2H), 4.1-4.0 (m, 4H), 3.6 (t, J = 7.0 Hz, 2H),3.5 (t, J = 6.6 Hz, 2H), 2.9 (t, J= 7.0 Hz, 2H), 2.7 (m, 1H), 2.5 - 2.4 (m, 2H), 2.2 - 2.1 (m, 3H), 2.1 - 2.0 (m, 1H), 1.8 - 1.7 (m, 2H), 1.3 - 1.2 (m, 6H). 13 C NMR (126MHz, CDCl3): d 143.7 (d, J = 8.6 Hz), 141.5, 139.5, 128.7 - 128.4 (m), 126.1, 125.3, 121.2, 113.5 (d, J = 10.9 Hz), 71.2, 70.6, 62.1 (dd, J = 30.7, 7.0 Hz), 44.1 (d, J = 135.8 Hz), 33.7 (d, J = 15.4 Hz), 32.7 (d, J = 3.6 Hz), 30.9, 30.3 (d, J = 3.6 Hz), 27.7, 16.6 (dd, J = 6.1, 3.0 Hz). 31 PNMR (162 MHz, CDCl3): d 29.0. HRMS (ESI) m / z ([M + H] + ) calcd for C 24 H 36 O4PS: 451.2066. Found: 451.2066. Example 17: Terminal alkyne 1q (13.2 mg, 0.10 mmol), α-bromophosphate ester 2a (50.3 mg, 0.15 mmol), bis(tricyclohexylphosphine)nickel chloride (10.3 mg, 0.015 mmol), 2,2'-bipyridine-4,4'-di-tert-butyl (5.4 mg, 0.02 mmol), methyldiethoxysilane (268.5 mg, 200 mol%), and potassium dihydrogen phosphate trihydrate (456.4 mg, 200 mol%) were added to a reaction flask, dissolved in a mixed solution of ethyl acetate and dimethyl sulfoxide (7:3, 1 mL), and reacted with stirring at 25 °C under nitrogen for 10 hours. After the reaction was completed, a saturated aqueous sodium bicarbonate solution (10 g) was added to quench the reaction, and dichloromethane (10 g) was added. After sufficient stirring, the mixture was allowed to stand for stratification. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated to obtain a brown crude product. The crude product was purified by column method (eluent: ethyl acetate / petroleum ether = 1:20, v / v) to obtain a colorless liquid target product 3q (18.6 mg, 0.048 mmol, yield 48%). 1 H NMR (400 MHz, CDCl3): d 7.36-7.32 (m, 2H),7.25-7.07 (m, 5H), 6.87-6.83 (m, 2H), 5.56 (d, J = 5.9 Hz, 1H), 5.42 (d, J = 5.4Hz, 1H), 4.07-3.96 (m, 4H), 3.82 (s, 3H), 3.00 (ddd, J = 23.4, 11.0, 3.9 Hz,1H), 2.86-2.75 (m, 1H), 2.57 (ddd, J = 13.7, 9.4, 7.1 Hz, 1H), 2.38-2.30 (m,1H), 2.22-2.11 (m, 1H), 1.21 (td, J = 15.6, 7.1 Hz, 6H). 13 C NMR (126 MHz, CDCl3): d 159.3, 143.5 (d, J = 8.2 Hz), 141.4, 135.4 (d, J = 5.4 Hz), 128.6, 128.5, 127.8,126.1, 115.3 (d, J = 9.5 Hz), 113.7, 62.7 (d, J= 7.3 Hz), 62.0 (d, J = 7.3 Hz),55.4, 42.1 (d, J = 137.2 Hz), 33.6 (d, J = 15.0 Hz), 32.2 (d, J = 3.6 Hz), 16.5(dd, J = 6.1, 2.5 Hz). 31 PNMR (162 MHz, CDCl3): d 29.0. HRMS (ESI) m / z ([M+H] + ) calcdfor C 22 H 30 O4P: 389.1876. Found: 389.1877. Embodiment 18: Terminal alkyne 1r (17.4 mg, 0.10 mmol), α-bromophosphate ester 2a (50.3 mg, 0.15 mmol), bis(tricyclohexylphosphine)nickel chloride (10.3 mg, 0.015 mmol), 2,2'-bipyridine-4,4'-di-tert-butyl (5.4 mg, 0.02 mmol), methyldiethoxysilane (268.5 mg, 200 mol%), and potassium dihydrogen phosphate trihydrate (456.4 mg, 200 mol%) were added to a reaction flask, dissolved in a mixed solution of ethyl acetate and dimethyl sulfoxide (7:3, 1 mL), and reacted with stirring at 25 °C under nitrogen for 10 hours. After the reaction was completed, saturated aqueous sodium bicarbonate solution (10 g) was added to quench the reaction, and dichloromethane (10 g) was added. After sufficient stirring, the mixture was allowed to stand for stratification. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated to obtain a brown crude product. The crude product was purified by column method (eluent: ethyl acetate / petroleum ether = 1:20, v / v) to obtain a colorless liquid target product 3r (25.8 mg, 0.060 mmol, yield 60%). 1 H NMR (500 MHz, CDCl3): d 7.30-7.25 (m, 2H),7.18 (t, J = 7.4 Hz, 2H), 7.15-7.07 (m, 4H), 6.99 (d, J = 8.5 Hz, 2H), 5.09 (t, J= 5.2 Hz, 2H), 4.03 - 3.93 (m, 4H), 2.72 - 2.64 (m, 3H), 2.56 - 2.40 (m, 4H), 2.17 - 2.09 (m, 1H), 2.03 - 1.95 (m, 1H), 1.21 - 1.17 (m, 6H). 13 C NMR (126 MHz, CDCl3): d 171.6, 150.8, 142.6 (d, J = 9.1 Hz), 141.3, 129.5, 128.5 (d, J = 7.3 Hz), 126.1, 125.9, 121.6, 114.1 (d, J = 10.4 Hz), 62.2 (dd, J = 21.6, 7.0 Hz), 44.1 (d, J = 136.2 Hz), 33.5 (d, J = 15.4 Hz), 32.4, 30.5 (dd, J = 92.2, 3.6 Hz), 16.5 (dd, J = 5.9, 2.7 Hz). 31 PNMR (202 MHz, CDCl3): d 28.5. HRMS (ESI) m / z ([M + H] + ) calcd for C 24 H 32 O5P: 431.1982. Found: 431.1981. Example 19: Terminal alkyne 1s (17.4 mg, 0.10 mmol), α-bromophosphate ester 2a (43.1 mg, 0.15 mmol), bis(tricyclohexylphosphine)nickel chloride (10.3 mg, 0.015 mmol), 2,2'-bipyridine-4,4'-di-tert-butyl (5.4 mg, 0.02 mmol), methyldiethoxysilane (268.5 mg, 200 mol%), and potassium dihydrogen phosphate trihydrate (456.4 mg, 200 mol%) were added to a reaction flask, dissolved in a mixed solution of ethyl acetate and dimethyl sulfoxide (7:3, 1 mL), and reacted with stirring at 25 °C under nitrogen for 10 hours. After the reaction was completed, saturated aqueous sodium bicarbonate solution (10 g) was added to quench the reaction, and dichloromethane (10 g) was added. After sufficient stirring, the mixture was allowed to stand for stratification. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated to obtain a brown crude product. The crude product was purified by column method (eluent: ethyl acetate / petroleum ether = 1:20, v / v) to obtain a colorless liquid target product 3s (18.7 mg, 0.049 mmol, yield 49%). 1 H NMR (400 MHz, CDCl3): d 8.01 (d, J = 9.6 Hz,2H), 7.54 (t, J = 7.4 Hz, 1H), 7.42 (t, J = 7.8 Hz, 2H), 5.14 (dd, J = 10.1, 5.1Hz, 2H), 4.47 (td, J = 6.8, 2.1 Hz, 2H), 4.13-4.02 (m, 4H), 2.76 -2.65 (m, 1H), 2.65-2.59 (m, 2H), 1.83-1.71 (m, 1H), 1.67-1.50 (m, 2H), 1.31-1.25 (m, 6H),0.89 (d, J = 6.5 Hz, 3H), 0.84 (d, J = 6.3 Hz, 3H). 13 C NMR (126 MHz, CDCl3): d 166.6,140.4 (d, J = 9.1 Hz), 133.0, 130.4, 129.7, 128.4, 115.5 (d, J = 11.8 Hz), 63.0,62.2 (dd, J = 31.6, 7.0 Hz), 42.9 (d, J= 135.8 Hz), 37.0 (d, J = 4.1 Hz), 34.3,25.3 (d, J = 14.5 Hz), 23.7, 21.2, 16.6 (dd, J = 5.9, 2.3 Hz). 31 PNMR (202 MHz,CDCl3): d 29.3. HRMS (ESI) m / z ([M+H] + ) calcd for C 20 H 32 O5P: 383.1982. Found:383.1981. Embodiment 20: Terminal alkyne 1t (30.9 mg, 0.10 mmol), α-bromophosphate ester 2a (50.3 mg, 0.15 mmol), bis(tricyclohexylphosphine)nickel chloride (10.3 mg, 0.015 mmol), 2,2'-bipyridine-4,4'-di-tert-butyl (5.4 mg, 0.02 mmol), methyldiethoxysilane (268.5 mg, 200 mol%), and potassium dihydrogen phosphate trihydrate (456.4 mg, 200 mol%) were added to a reaction flask, dissolved in a mixed solution of ethyl acetate and dimethyl sulfoxide (7:3, 1 mL), and reacted with stirring at 25 °C under nitrogen for 10 hours. After the reaction was completed, saturated sodium bicarbonate aqueous solution (10 g) was added to quench the reaction, and dichloromethane (10 g) was added. After sufficient stirring, the mixture was allowed to stand for stratification. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated to obtain a brown crude product. The crude product was purified by column method (eluent: ethyl acetate / petroleum ether = 1:20, v / v) to obtain a colorless liquid target product 3t (29.4 mg, 0.052 mmol, yield 52%). 1 H NMR (400 MHz, CDCl3): d 7.77 (d, J = 8.3 Hz,2H), 7.39-7.27 (m, 5H), 7.23-7.20 (m, 2H), 6.73 (d, J = 4.0 Hz, 1H), 6.17 (d, J =4.0 Hz, 1H), 5.22 (d, J = 5.3 Hz, 1H), 5.19 (d, J = 4.9 Hz, 1H), 4.38 (td, J= 6.8, 1.8 Hz, 2H), 4.18 - 4.10 (m, 4H), 4.01 (s, 3H), 3.78 (s, 2H), 2.79 (td, J = 9.4, 4.8 Hz, 1H), 2.60 (dt, J = 5.5, 2.8 Hz, 3H), 2.54 (dd, J = 10.9, 3.9 Hz, 1H), 2.49 (s, 3H), 2.26 (ddd, J = 9.8, 6.5, 2.9 Hz, 1H), 2.12 - 2.06 (m, 1H), 1.36 (d, J = 5.9 Hz, 6H). 13 C NMR (126 MHz, CDCl3): d 186.0, 169.4, 142.0, 141.2, 139.9 (d, J = 9.1 Hz), 137.4, 134.4, 131.5, 129.5, 128.8, 128.5 (d, J = 6.4 Hz), 126.2, 122.3, 115.8, 109.6, 63.4, 62.3 (dd, J = 13.4, 7.0 Hz), 43.9 (d, J = 136.1 Hz), 34.6, 33.5 (d, J = 15.0 Hz), 33.3, 33.0, 29.9 (d, J = 3.6 Hz), 21.6, 16.6 (dd, J = 5.9, 3.2 Hz). 31 PNMR (202 MHz, CDCl3): d 28.3. HRMS (ESI) m / z ([M + H] + ) calcd for C 32 H 41 NO6P: 566.2666. Found: 566.2667. Example 21: Terminal alkyne 1a (17.4 mg, 0.10 mmol), α-bromophosphate ester 2b (54.5 mg, 0.15 mmol), bis(tricyclohexylphosphine)nickel chloride (10.3 mg, 0.015 mmol), 2,2'-bipyridine-4,4'-di-tert-butyl (5.4 mg, 0.02 mmol), methyldiethoxysilane (268.5 mg, 200 mol%), and potassium dihydrogen phosphate trihydrate (456.4 mg, 200 mol%) were added to a reaction flask, dissolved in a mixed solution of ethyl acetate and dimethyl sulfoxide (7:3, 1 mL), and reacted with stirring at 25 °C under nitrogen for 10 hours. After the reaction was completed, saturated sodium bicarbonate aqueous solution (10 g) was added to quench the reaction, and dichloromethane (10 g) was added. After sufficient stirring, the mixture was allowed to stand for stratification. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated to obtain a brown crude product. The crude product was purified by column method (eluent: ethyl acetate / petroleum ether = 1:20, v / v) to obtain a colorless liquid target product 3u (35.7 mg, 0.078 mmol, yield 78%). 1 H NMR (400 MHz, CDCl3): d 8.06-7.98 (m, 2H),7.56-7.50 (m, 1H), 7.40 (t, J = 7.7 Hz, 2H), 7.26-7.11 (m, 5H), 5.21 (d, J = 4.6Hz, 1H), 5.15 (d, J = 5.1 Hz, 1H), 4.73-4.58 (m, 2H), 4.55-4.40 (m, 2H), 2.78-2.69 (m, 1H), 2.68-2.60 (m, 2H), 2.57-2.41 (m, 2H), 2.25-2.11 (m, 1H), 2.04-1.98 (m, 1H), 1.27 (dd, J = 6.3, 3.1 Hz, 9H), 1.22 (d, J = 6.2 Hz, 3H). 13 C NMR (101MHz, CDCl3): d 166.6, 141.4, 140.3 (d, J = 8.9 Hz), 133.0, 130.4, 129.7, 128.6-128.4 (m), 126.1, 115.5 (d, J = 11.2 Hz), 70.5 (dd, J= 16.7, 7.2 Hz), 63.0, 44.9(d, J = 137.5 Hz), 34.7, 33.6 (d, J = 15.4 Hz), 29.8 (d, J = 3.5 Hz), 24.5-23.8(m). 31 PNMR (202 MHz, CDCl3): d 26.5. HRMS (ESI) m / z ([M+H] + ) calcd for C 26 H 36 O5P:459.2295. Found: 459.2295. Embodiment 22: Terminal alkyne 1a (17.4 mg, 0.10 mmol), α-bromophosphate 2c (49.1 mg, 0.15 mmol), bis(tricyclohexylphosphine)nickel chloride (10.3 mg, 0.015 mmol), 2,2'-bipyridine-4,4'-di-tert-butyl (5.4 mg, 0.02 mmol), methyldiethoxysilane (268.5 mg, 200 mol%), and potassium dihydrogen phosphate trihydrate (456.4 mg, 200 mol%) were added to a reaction flask, dissolved in a mixed solution of ethyl acetate and dimethyl sulfoxide (7:3, 1 mL), and reacted with stirring at 25 °C under nitrogen for 10 hours. After the reaction was completed, a saturated aqueous sodium bicarbonate solution (10 g) was added to quench the reaction, and dichloromethane (10 g) was added. After sufficient stirring, the mixture was allowed to stand for stratification. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated to obtain a brown crude product. The crude product was purified by column method (eluent: ethyl acetate / petroleum ether = 1:20, v / v) to obtain a colorless liquid target product 3v (25.3 mg, 0.060 mmol, yield 60%). 1 H NMR (500 MHz, CDCl3): d 8.02 (d, J = 7.0 Hz,2H), 7.58-7.50 (m, 1H), 7.42 (t, J = 7.8 Hz, 2H), 5.12-5.06 (m, 2H), 4.74-4.62(m, 2H), 4.53-4.40 (m, 2H), 2.60 (t, J= 7.7 Hz, 2H), 2.36 - 2.18 (m, 2H), 2.06 - 1.97 (m, 1H), 1.85 - 1.75 (m, 1H), 1.72 - 1.61 (m, 1H), 1.60 - 1.50 (m, 2H), 1.49 - 1.41 (m, 1H), 1.32 - 1.26 (m, 13H), 1.14 - 1.02 (m, 1H). 13 C NMR (126 MHz, CDCl3): d 166.6, 142.2 (d, J = 8.2 Hz), 133.0, 130.4, 129.7, 128.4, 114.9 (d, J = 11.4 Hz), 70.3 (dd, J = 76.7, 7.3 Hz), 63.2, 51.7 (d, J = 135.7 Hz), 40.6, 32.6 - 32.2 (m), 25.3, 24.5 (d, J = 3.6 Hz), 24.3 - 23.8 (m). 31 PNMR (202 MHz, CDCl3): d 26.6. HRMS (ESI)m / z ([M + H] + ) calcd for C 23 H 36 O5P: 423.2295. Found: 423.2296. Example 23: Terminal alkyne 1a (17.4 mg, 0.10 mmol), α-bromophosphate ester 2d (51.2 mg, 0.15 mmol), bis(tricyclohexylphosphine)nickel chloride (10.3 mg, 0.015 mmol), 2,2'-bipyridine-4,4'-di-tert-butyl (5.4 mg, 0.02 mmol), methyldiethoxysilane (268.5 mg, 200 mol%), and potassium dihydrogen phosphate trihydrate (456.4 mg, 200 mol%) were added to a reaction flask, dissolved in a mixed solution of ethyl acetate and dimethyl sulfoxide (7:3, 1 mL), and reacted with stirring at 25 °C under nitrogen for 10 hours. After the reaction was completed, saturated aqueous sodium bicarbonate solution (10 g) was added to quench the reaction, and dichloromethane (10 g) was added. After sufficient stirring, the mixture was allowed to stand for stratification. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated to obtain a brown crude product. The crude product was purified by column method (eluent: ethyl acetate / petroleum ether = 1:20, v / v) to obtain a colorless liquid target product 3w (36.2 mg, 0.083 mmol, yield 83%). 1 H NMR (500 MHz, CDCl3): d 8.02 (d, J = 7.5 Hz,2H), 7.53 (t, J = 7.5 Hz, 1H), 7.41 (t, J = 7.8 Hz, 2H), 5.11 (dd, J = 7.6, 4.1 Hz,2H), 4.74-4.61 (m, 2H), 4.46 (t, J = 6.9 Hz, 2H), 2.61-2.47 (m, 2H), 2.28 (dd, J = 22.4, 9.1 Hz, 1H), 2.11 (d, J = 13.0 Hz, 1H), 1.89-1.78 (m, 2H), 1.76-1.55(m, 4H), 1.28 (td, J = 13.1, 6.2 Hz, 12H), 1.20-1.08 (m, 3H), 0.94-0.84 (m,1H). 13 C NMR (126 MHz, CDCl3): d 166.6, 141.0 (d, J = 7.7 Hz), 133.0, 130.4, 129.7,128.4, 115.3 (d, J = 10.4 Hz), 70.5 (d, J= 7.3 Hz), 69.9 (d, J = 7.3 Hz), 63.1,52.3 (d, J = 136.5 Hz), 38.4 (d, J = 3.2 Hz), 35.6, 32.6 (d, J = 5.0 Hz), 31.6 (d, J = 13.6 Hz), 26.7-26.2 (m), 24.7-23.6 (m). 31 PNMR (202 MHz, CDCl3): d 26.7. HRMS (ESI) m / z ([M+H] + ) calcd for C 24 H 38 O5P: 437.2451. Found: 437.2451. Embodiment 24: Terminal alkyne 1a (17.4 mg, 0.10 mmol), α-bromophosphate ester 2e (47.3 mg, 0.15 mmol), bis(tricyclohexylphosphine)nickel chloride (10.3 mg, 0.015 mmol), 2,2'-bipyridine-4,4'-di-tert-butyl (5.4 mg, 0.02 mmol), methyldiethoxysilane (268.5 mg, 200 mol%), and potassium dihydrogen phosphate trihydrate (456.4 mg, 200 mol%) were added to a reaction flask, dissolved in a mixed solution of ethyl acetate and dimethyl sulfoxide (7:3, 1 mL), and reacted with stirring at 25 °C under nitrogen for 10 hours. After the reaction was completed, a saturated aqueous sodium bicarbonate solution (10 g) was added to quench the reaction, and dichloromethane (10 g) was added. After sufficient stirring, the mixture was allowed to stand for stratification. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated to obtain a brown crude product. The crude product was purified by column method (eluent: ethyl acetate / petroleum ether = 1:20, v / v) to obtain a colorless liquid target product 3x (29.1 mg, 0.071 mmol, yield 71%). 1 H NMR (500 MHz, CDCl3): d 8.02 (dd, J = 8.4, 1.4Hz, 2H), 7.57-7.50 (m, 1H), 7.41 (t, J = 7.8 Hz, 2H), 5.14 (d, J = 4.7 Hz, 1H),5.10 (d, J= 5.3 Hz, 1H), 4.74 - 4.62 (m, 2H), 4.52 - 4.42 (m, 2H), 2.62 (t, J = 6.0Hz, 2H), 2.44 (ddd, J = 23.7, 11.4, 3.7 Hz, 1H), 1.89 - 1.79 (m, 1H), 1.74 - 1.64(m, 1H), 1.43 - 1.13 (m, 16H), 0.83 (t, J = 7.1 Hz, 3H). 13 C NMR (126 MHz, CDCl3): d 166.6, 140.6 (d, J = 9.1 Hz), 133.0, 130.4, 129.7, 128.4, 115.2 (d, J = 11.4 Hz),70.3 (dd, J = 22.7, 7.3 Hz), 63.0, 45.5 (d, J = 137.3 Hz), 34.8 (d, J = 3.2 Hz),29.9 (d, J = 15.4 Hz), 27.9 (d, J = 4.1 Hz), 24.4 - 23.8 (m), 22.6, 14.0. 31 PNMR (202MHz, CDCl3): d 27.1. HRMS (ESI) m / z ([M + H] + ) calcd for C 22 H 36 O5P: 411.2295. Found:411.2296. Example 25: Terminal alkyne 1a (17.4 mg, 0.10 mmol), α-bromophosphate ester 2f (64.8 mg, 0.15 mmol), bis(tricyclohexylphosphine)nickel chloride (10.3 mg, 0.015 mmol), 2,2'-bipyridine-4,4'-di-tert-butyl (5.4 mg, 0.02 mmol), methyldiethoxysilane (268.5 mg, 200 mol%), and potassium dihydrogen phosphate trihydrate (456.4 mg, 200 mol%) were added to a reaction flask, dissolved in a mixed solution of ethyl acetate and dimethyl sulfoxide (7:3, 1 mL), and reacted with stirring at 25 °C under nitrogen for 10 hours. After the reaction was completed, saturated aqueous sodium bicarbonate solution (10 g) was added to quench the reaction, and dichloromethane (10 g) was added. After sufficient stirring, the mixture was allowed to stand for stratification. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated to obtain a brown crude product. The crude product was purified by column method (eluent: ethyl acetate / petroleum ether = 1:20, v / v) to obtain a colorless liquid target product 3y (39.5 mg, 0.075 mmol, yield 75%). 1 H NMR (400 MHz, CDCl3): d 8.02 (dd, J = 8.4, 1.4Hz, 2H), 7.81 (dd, J = 5.4, 3.1 Hz, 2H), 7.69 (dd, J = 5.4, 3.1 Hz, 2H), 7.52 (t, J = 7.4 Hz, 1H), 7.40 (t, J = 7.6 Hz, 2H), 5.23 (d, J = 5.6 Hz, 2H), 4.66 (h, J =6.3 Hz, 2H), 4.51 (t, J = 6.7 Hz, 2H), 3.78-3.63 (m, 2H), 2.72 (t, J = 6.8 Hz,2H), 2.56 (ddd, J = 24.3, 11.3, 3.8 Hz, 1H), 2.29-2.19 (m, 1H), 2.16-2.04 (m,1H), 1.29-1.25 (m, 12H). 13 C NMR (126 MHz, CDCl3): d 168.3, 166.6, 139.7 (d, J= 9.1Hz), 134.1, 132.9, 132.2, 130.4, 129.7, 128.4, 123.3, 115.7 (d, J = 11.4 Hz),70.8 (dd, J = 7.3, 3.2 Hz), 63.0, 43.4 (d, J = 139.3 Hz), 36.4 (d, J = 18.2 Hz),34.6, 27.1 (d, J = 3.6 Hz), 24.2 (dd, J = 6.6, 3.4 Hz), 24.0 (dd, J = 7.9, 5.2 Hz). 31 PNMR (162 MHz, CDCl3): d 25.2. HRMS (ESI) m / z ([M+H] + ) calcd for C 28 H 35 NO7P:528.2146. Found: 528.2148. Embodiment 26: Terminal alkyne 1a (17.4 mg, 0.10 mmol), α-bromophosphate 2 g (55.1 mg, 0.15 mmol), bis(tricyclohexylphosphine)nickel chloride (10.3 mg, 0.015 mmol), 2,2'-bipyridine-4,4'-di-tert-butyl (5.4 mg, 0.02 mmol), methyldiethoxysilane (268.5 mg, 200 mol%), and potassium dihydrogen phosphate trihydrate (456.4 mg, 200 mol%) were added to a reaction flask, dissolved in a mixed solution of ethyl acetate and dimethyl sulfoxide (7:3, 1 mL), and reacted with stirring at 25 °C under nitrogen for 10 hours. After the reaction was completed, saturated aqueous sodium bicarbonate solution (10 g) was added to quench the reaction, and dichloromethane (10 g) was added. After sufficient stirring, the mixture was allowed to stand for stratification. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated to obtain a brown crude product. The crude product was purified by column method (eluent: ethyl acetate / petroleum ether = 1:20, v / v) to obtain a colorless liquid target product 3z (19.4 mg, 0.074 mmol, yield 74%). 1 H NMR (400 MHz, CDCl3): d 8.02 (d, J = 8.6 Hz,2H), 7.54 (t,J = 7.4 Hz, 1H), 7.41 (t, J = 7.7 Hz, 2H), 5.85 - 5.80 (m, 2H), 5.19(d, J = 4.9 Hz, 1H), 5.15 (d, J = 5.3 Hz, 1H), 4.67 (dt, J = 12.0, 6.1 Hz, 2H),4.51 - 4.40 (m, 2H), 2.73 - 2.62 (m, 3H), 2.56 - 2.45 (m, 2H), 2.21 (s, 4H), 2.02(ddq, J = 11.4, 5.8, 3.2 Hz, 1H), 1.31 - 1.24 (m, 12H). 13 C NMR (126 MHz, CDCl3): d 166.6, 153.1, 150.6, 140.2 (d, J = 9.1 Hz), 133.0, 130.4, 129.7, 128.4, 115.5(d, J = 11.4 Hz), 106.1 (d, J = 40.0 Hz), 70.5 (dd, J = 17.9, 7.0 Hz), 63.0, 44.4(d, J = 138.1 Hz), 34.9, 26.8 (d, J = 3.6 Hz), 25.9 (d, J = 15.9 Hz), 24.4 - 23.8(m), 13.6. 31 PNMR (162 MHz, CDCl3): d 26.5. HRMS (ESI) m / z ([M + H] + ) calcd forC 25 H 36 O6P: 463.2244. Found: 463.2245. Example 27: Terminal alkyne 1a (17.4 mg, 0.10 mmol), benzyl bromide 2h (34.3 mg, 0.15 mmol), bis(tricyclohexylphosphine)nickel chloride (10.3 mg, 0.015 mmol), 2,2'-bipyridine-4,4'-di-tert-butyl (5.4 mg, 0.02 mmol), methyldiethoxysilane (268.5 mg, 200 mol%), and potassium dihydrogen phosphate trihydrate (456.4 mg, 200 mol%) were added to a reaction flask, dissolved in a mixed solution of ethyl acetate and dimethyl sulfoxide (7:3, 1 mL), and reacted with stirring at 25 °C under nitrogen for 10 hours. After the reaction was completed, saturated aqueous sodium bicarbonate solution (10 g) was added to quench the reaction, and dichloromethane (10 g) was added. After sufficient stirring, the mixture was allowed to stand for stratification. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated to obtain a brown crude product. The crude product was purified by column method (eluent: ethyl acetate / petroleum ether = 1:20, v / v) to obtain a colorless liquid target product 3za (18.8 mg, 0.058 mmol, yield 58%). 1 H NMR (400 MHz, CDCl3): d 8.03 (dd, J = 8.4, 1.4 Hz, 2H), 7.61-7.52 (m, 1H), 7.44 (t, J = 7.6 Hz, 2H), 6.70 (d, J = 2.1 Hz, 1H), 6.16 (d, J = 3.8Hz, 1H), 5.04 (s, 1H), 4.97 (s, 1H), 4.44 (t, J = 6.6 Hz, 2H), 3.49 (s, 2H), 2.58-2.47 (m, 2H). 13 C NMR (126 MHz, CDCl3): d 166.6, 156.5, 141.0, 133.1, 130.3,129.7, 128.5, 115.2, 112.6 (q, J = 2.9 Hz), 107.8, 63.0, 35.3, 34.7. HRMS (ESI)m / z ([M+H] + ) calcd for C 17 H 16 F3O3: 325.1046. Found: 325.1047. Embodiment 28: Terminal alkyne 1a (17.4 mg, 0.10 mmol), benzyl bromide 2i (40.8 mg, 0.15 mmol), bis(tricyclohexylphosphine)nickel chloride (10.3 mg, 0.015 mmol), 2,2'-bipyridine-4,4'-di-tert-butyl (5.4 mg, 0.02 mmol), methyldiethoxysilane (268.5 mg, 200 mol%), and potassium dihydrogen phosphate trihydrate (456.4 mg, 200 mol%) were added to a reaction flask, dissolved in a mixed solution of ethyl acetate and dimethyl sulfoxide (7:3, 1 mL), and reacted with stirring at 25 °C under nitrogen for 10 hours. After the reaction was completed, saturated aqueous sodium bicarbonate solution (10 g) was added to quench the reaction, and dichloromethane (10 g) was added. After sufficient stirring, the mixture was allowed to stand for stratification. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated to obtain a brown crude product. The crude product was purified by column method (eluent: ethyl acetate / petroleum ether = 1:20, v / v) to obtain a colorless liquid target product 3zb (23.9 mg, 0.065 mmol, yield 65%). 1 H NMR (400 MHz, CDCl3): d 8.04 (dd, J = 8.4, 1.4 Hz, 2H), 7.76(dd, J = 7.8, 1.5 Hz, 1H), 7.64 (td, J = 7.8, 1.5 Hz, 1H), 7.58-7.53 (m, 1H),7.51 (dd, J = 8.4, 2.3 Hz, 3H), 7.47-7.40 (m, 3H), 7.34 (d, J = 8.4 Hz, 2H), 5.02(s, 1H), 4.96 (s, 1H), 4.46 (t, J = 6.8 Hz, 2H), 3.50 (s, 2H), 2.55-2.45 (m,2H). 13 C NMR (126 MHz, CDCl3): d 166.7, 145.4, 144.5, 140.0, 136.3, 133.9, 133.0(d, J = 14.5 Hz), 130.4, 130.2, 129.7, 129.5, 128.9, 128.5, 127.5, 118.9,114.2, 111.3, 63.2, 42.9, 34.6. HRMS (ESI) m / z ([M+H] +) calcd for C 25 H 22 NO2:368.1645. Found: 368.1646. Embodiment 29: Terminal alkyne 1a (17.4 mg, 0.10 mmol), benzyl bromide 2j (38.2 mg, 0.15 mmol), bis(tricyclohexylphosphine)nickel chloride (10.3 mg, 0.015 mmol), 2,2'-bipyridine-4,4'-di-tert-butyl (5.4 mg, 0.02 mmol), methyldiethoxysilane (268.5 mg, 200 mol%), and potassium dihydrogen phosphate trihydrate (456.4 mg, 200 mol%) were added to a reaction flask, dissolved in a mixed solution of ethyl acetate and dimethyl sulfoxide (7:3, 1 mL), and reacted with stirring at 25 °C under nitrogen for 10 hours. After the reaction was completed, saturated aqueous sodium bicarbonate solution (10 g) was added to quench the reaction, and dichloromethane (10 g) was added. After sufficient stirring, the mixture was allowed to stand for stratification. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated to obtain a brown crude product. The crude product was purified by column method (eluent: ethyl acetate / petroleum ether = 1:20, v / v) to obtain a colorless liquid target product 3zc (17.5 mg, 0.050 mmol, yield 50%). 1 H NMR (400 MHz, CDCl3): d 8.02 (dd, J = 8.4, 1.5 Hz, 2H), 7.56(t, J = 7.4 Hz, 1H), 7.44 (t, J = 7.8 Hz, 2H), 7.23 (d, J = 8.6 Hz, 2H), 7.14 (d, J =7.9 Hz, 2H), 5.00 (s, 1H), 4.89 (s, 1H), 4.43 (t, J = 6.8 Hz, 2H), 3.43 (s,2H), 2.44 (t, J = 6.8 Hz, 2H). 13 C NMR (126 MHz, CDCl3): d 166.6, 144.4, 138.0,133.1, 130.4 (d, J = 3.3 Hz), 129.7, 128.5, 121.1, 114.2, 63.1, 42.4, 34.5. HRMS(ESI) m / z ([M+H] + ) calcd for C 19 H 18 F3O3: 351.1203. Found: 351.1203. Embodiment 30: Terminal alkyne 1a (17.4 mg, 0.10 mmol), benzyl bromide 2k (30.1 mg, 0.15 mmol), bis(tricyclohexylphosphine)nickel chloride (10.3 mg, 0.015 mmol), 2,2'-bipyridine-4,4'-di-tert-butyl (5.4 mg, 0.02 mmol), methyldiethoxysilane (268.5 mg, 200 mol%), and potassium dihydrogen phosphate trihydrate (456.4 mg, 200 mol%) were added to a reaction flask, dissolved in a mixed solution of ethyl acetate and dimethyl sulfoxide (7:3, 1 mL), and reacted with stirring at 25 °C under nitrogen for 10 hours. After the reaction was completed, saturated aqueous sodium bicarbonate solution (10 g) was added to quench the reaction, and dichloromethane (10 g) was added. After sufficient stirring, the mixture was allowed to stand for stratification. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated to obtain a brown crude product. The crude product was purified by column method (eluent: ethyl acetate / petroleum ether = 1:20, v / v) to obtain a colorless liquid target product 3zd (24.9 mg, 0.084 mmol, yield 84%). 1 H NMR (400 MHz, CDCl3): d 8.04 (d, J = 8.4 Hz, 2H), 7.56 (t, J =7.4 Hz, 1H), 7.44 (t, J = 7.6 Hz, 2H), 7.25-7.19 (m, 1H), 6.84-6.75 (m, 3H), 4.99 (s, 1H), 4.93 (s, 1H), 4.43 (t, J = 6.8 Hz, 2H), 3.79 (s, 3H), 3.42 (s,2H), 2.46 (t, J = 6.8 Hz, 2H). 13 C NMR (126 MHz, CDCl3): d 166.6, 159.8, 144.7,140.9, 133.0, 130.4, 129.7, 129.4, 128.4, 121.5, 114.7, 113.8, 111.7, 63.2,55.2, 43.3, 34.4. HRMS (ESI) m / z ([M+H] + ) calcd for C 19 H 21 O3: 297.1485. Found:297.1485. In addition, it should be understood that after reading the above description of the present invention, those skilled in the art may make various changes or modifications to the present invention, and these equivalent forms also fall within the scope defined by the claims attached to this application.

Claims

1. A method for synthesizing 1,1-dialkyl substituted olefins, characterized in that: The synthesis method comprises the following steps: Terminal alkyne 1, alkyl bromide 2, catalyst, ligand, hydrogen source, base, and solvent are mixed and subjected to coupling reaction in a nitrogen atmosphere to obtain 1,1-dialkyl substituted olefin 3; the synthetic route is as follows: Wherein, R is an alkyl group, an aryl group or a heteroaryl group; R 1 and R 2 Each of the following is independently selected from hydrogen, alkyl, cycloalkyl, phosphate or benzyl.

2. The synthesis method according to claim 1, characterized in that The catalyst is selected from one of NiF2, NiI2, Ni(acac)2, NiCl2(PPh3)2, NiCl2(PCy3)2, Ni(dppf)Cl2, Ni(TMHD)2, Ni(COD)2, and Ni(OTf)2.

3. The synthesis method according to claim 1, characterized in that The ligand is a nitrogen ligand or a phosphorus ligand; wherein the nitrogen ligand is selected from one of 2,2'-bipyridine-4,4'-dicarboxylic acid, 2,2'-bipyridine-4,4'-dimethyl, 2,2'-bipyridine-4,4'-di-tert-butyl, 2,2'-bipyridine-4,4'-dimethoxy, 1,10-phenanthroline, and 2,9-dimethyl-1,10-phenanthroline; and the phosphorus ligand is selected from one of 1,2-bis(diphenylphosphino)ethane and 1,2-bis(dimethylphosphino)ethane.

4. The synthesis method according to claim 1, characterized in that The hydrogen source is one of methyldiethoxysilane, diethylsilane, triethylsilane, diphenylsilane and triethoxysilane.

5. The synthesis method according to claim 1, characterized in that The base is an organic base or an inorganic base, wherein the organic base is one of 4-dimethylaminopyridine, N,N-diisopropylethylamine, triethylamine, and DBU (1,8-diazabicyclo[5.4.0]undec-7-ene); the inorganic base is one of Na2CO3, Cs2CO3, K2CO3, Li2CO3, K2PO4, and K2HPO4•3H2O.

6. The synthesis method according to claim 1, characterized in that The solvent is one or two of N-methylpyrrolidone, N,N-dimethylformamide, N,N-dimethylacetamide, tetrahydrofuran, toluene, dimethyl sulfoxide and ethyl acetate.

7. The synthesis method according to claim 1, characterized in that The molar ratio of the terminal alkyne 1, the alkyl bromide 2, the catalyst, the ligand, the hydrogen source and the base is 1-3:1-3:0.05-0.2:0.05-0.3:1-10:1-10.

8. The synthesis method according to claim 7, characterized in that The molar ratio of the terminal alkyne 1, the alkyl bromide 2, the catalyst, the ligand, the hydrogen source and the base is 1.5:1:0.15:0.2:2:

2.

9. The synthesis method according to claim 1, characterized in that The temperature of the coupling reaction is 0-100°C.

10. The synthesis method according to claim 1, characterized in that The coupling reaction time is 1 to 24 hours.

Images