Method for synthesizing non-cyclic and non-terminal vicinal diol derivative based on propargyl alcohol ester

Abstract

The invention discloses a method for synthesizing a non-cyclic and non-terminal vicinal diol derivative based on propargyl alcohol ester. Through a coupling strategy that propargyl alcohol ester and an exogenous nucleophilic reagent are catalyzed by transition metal (palladium), construction of a bimolecular exogenous nucleophilic group substituted allyl skeleton is realized. The strategy breaks through the dilemma that alkenylation products are limited to construction of cyclic molecules at the present stage and the tail ends of the alkenylation products are limited, and a reform synthesis scheme is provided for selective conversion of propargyl alcohol ester catalyzed by transition metal. The selected catalyst and ligand are wide in source, and the substrate is cheap and easy to obtain; the method provided by the invention has the advantages of high selectivity, excellent stereoselectivity and good functional group compatibility, can be suitable for structural modification of bioactive molecules and intermediates, is a simple and efficient asymmetric catalysis strategy for synthesizing non-cyclic and non-terminal vicinal diol derivatives, and has a good application prospect.

Description

Technical Field

[0001] This invention belongs to the fields of catalytic synthesis technology and fine chemical synthesis, and relates to a method for synthesizing acyclic, non-terminated vicinal diol derivatives based on propargyl alcohol esters. Background Technology

[0002] vicinal diols are an important class of fine chemicals with significant applications in cosmetics, pharmaceuticals, pesticides, surfactants, polyesters, and inks. For a long time, the efficient and selective synthesis of vicinal diol derivatives has been a major focus for chemists. However, achieving highly enantioselective synthesis of vicinal diol derivatives based on catalytic asymmetry remains a long-standing scientific challenge. Currently, the preparation of dihydroxy compounds from alkenes is a common functional group transformation method in organic synthesis, such as the potassium osmium tetroxide method, Upjohn dihydroxylation, and Sharpless asymmetric dihydroxylation. However, most of these methods are limited by the use of toxic and expensive stoichiometric osmium reagents, long reaction times, the tendency for vicinal diols to be further oxidized to vicinal diketones under certain reaction conditions, and low yields. Transition metal-catalyzed selective alkenylation of propargyl esters and nucleophilic substitution of carboxylic acids to construct carbon-carbon / heterobonds is an effective strategy for synthesizing vicinal diol derivatives. However, due to the stable -COO structure of carboxylic acids... - Not only is nucleophilic substitution difficult, but acidic H ions can quench nucleophilic reactive species, making it difficult for carboxylic acids to undergo nucleophilic substitution reactions directly.

[0003] Currently, the selective alkenylation of propargyl esters mainly employs a cyclization strategy to achieve the synthesis of a single product. The primary strategies involve coupling propargyl esters with intramolecular nucleophilic sites with exogenous nucleophiles, or sequential nucleophilic substitution of conventional propargyl esters with binary nucleophiles. Furthermore, these strategies typically utilize five- or six-membered ring structures with low angle strain, thus possessing inherent thermodynamic stability and facilitating highly selective construction. While this cyclization-based strategy largely avoids the side reactions of conjugated dienylation, the formation of cyclic structures also limits its application. To avoid steric symmetry of the alkenylated product... Z / E Isomerization is largely limited by strategies that rely on propargyl esters with hindered conjugated dienylation, resulting in the construction of terminal-restricted products. Therefore, developing a universally applicable strategy for the alkenylation of propargyl esters to achieve highly stereo, regio, and chemoselective construction of acyclic, multi-substituted vicinal diol derivatives is of great practical significance and scientific research value. Summary of the Invention

[0004] To address the problems existing in the prior art, this invention provides a method for synthesizing acyclic, non-terminated vicinal diol derivatives based on propargyl esters. This method utilizes a transition metal (palladium)-catalyzed coupling strategy between propargyl esters and exogenous nucleophiles to construct a bimolecular allyl skeleton substituted with exogenous nucleophilic groups. This strategy overcomes the current limitations of alkenylation products, which are restricted to cyclic molecules and terminal-restricted products, providing a revolutionary synthetic approach for the selective conversion of propargyl esters catalyzed by transition metals.

[0005] To address the problems in the existing technology, the technical solution adopted by this invention is as follows: A method for synthesizing acyclic, non-terminated vicinal diol derivatives based on propargyl esters, wherein propargyl esters are used in a solvent. and carboxylic acid / phenol nucleophiles (Nu-H) or Using palladium as the reaction substrate, a catalytic system of transition metal and organophosphorus ligand ligand was employed in a base environment. After the reaction was completed, the acyclic, non-terminated vicinal diol derivative was obtained. or Wherein: the molar ratio of propargyl ester, carboxylic acid / phenol, transition metal palladium, and base is 1:(1-2):(0.01-0.2):(1-5); R 1 R 2 With R 4 R indicates alkyl or aryl. 3 It represents an aryl group.

[0006] The general formula for the reaction is as follows:

[0007] Preferably, the substituents of the alkyl group are each independently selected from hydrogen, C1-C20 alkyl, C1-C20 haloalkyl, C1-C20 alkylcarbonyl, nitro, hydroxyl, ester, alkenyl, ether, amide, silyl, mercapto, amino, or cyano; the aryl group represents biphenyl, naphthyl, anthracene, and heteroaryl groups containing N, O, or S, whose benzene ring is substituted or unsubstituted by alkyl, C1-C20 haloalkyl, C1-C20 alkylcarbonyl, nitro, hydroxyl, ester, alkenyl, ether, amide, silyl, mercapto, amino, or cyano groups.

[0008] Preferably, the carboxylic acid / phenol nucleophile is selected from one or more of alkyl carboxylic acids / phenol, aryl carboxylic acids / phenol, amino carboxylic acids / phenol, alkoxy carboxylic acids / phenol, aryloxy carboxylic acids / phenol, and arylalkyl carboxylic acids / phenol.

[0009] Preferably, the organophosphine ligand is a bidentate N ligand, a bidentate P ligand, a bidentate NP ligand, a monodentate N ligand, a monodentate phosphine ligand, a tridentate NPN ligand, a tridentate NSP ligand, or a tridentate N ligand.

[0010] More preferably, the organophosphorus ligand is an oxazoline ligand, a diamine ligand, a monodentate phosphine ligand, a phosphoramide ligand, a biphenyl bidentate phosphine ligand, a spirocyclic bidentate phosphine ligand, a binatate bidentate phosphine ligand, or a sulfinamide-substituted phosphine ligand.

[0011] More preferably, the organophosphorus ligand is a biphenyl bidentate phosphorus ligand, a chain bidentate phosphorus ligand, a binatane bidentate phosphorus ligand, or a bidentate phosphorus ligand with a ferrocene framework.

[0012] Preferably, the base is selected from one or more of sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium methoxide, potassium ethoxide, potassium tert-butoxide, sodium tert-pentoxide, potassium tert-pentoxide, sodium borohydride, sodium cyanoborohydride, lithium aluminum hydride, lithium methoxy, potassium carbonate, sodium carbonate, sodium hydroxide, cesium carbonate, potassium phosphate, triethylamine, DBU (1,8-diazobicyclo[5.4.0]undecyl-7-ene), triethylenediamine, TBD (1,5,7-triazidobicyclo(4.4.0)decyl-5-ene), and tetramethylguanidine.

[0013] More preferably, the base is DBU (1,8-diazobisspirocyclo[5.4.0]undecyl-7-ene), sodium tert-butoxide, triethylamine, triethylenediamine, potassium phosphate, lithium methoxy, or sodium hydroxide.

[0014] More preferably, the base is DBU (1,8-diazobisspirocyclic [5.4.0]undecyl-7-ene).

[0015] Preferably, the palladium is selected from palladium chloride, palladium bromide, palladium iodide, palladium acetate, palladium neopentanoate, bis(triphenylphosphine)acetate, 1,2-bis(diphenylphosphine)ethane palladium chloride, (1,1'-bis(diphenylphosphine)ferrocene)dichloride palladium, palladium acetylacetone, bis(hexafluoroacetylacetone)palladium, bis(triphenylphosphine)dichloride palladium, tetra(triphenylphosphine)palladium, bis(tri-tert-butylphosphine)palladium, bis(dibenzylacetone)palladium, chloro(crotonyl)(tricyclohexylphosphine)palladium, and tri(dibenzylacetone)palladium. One or more of the following: dipalladium, tris(dibenzylacetone)dipalladium-chloroform adduct, (1,5-cyclooctadiene)palladium dibromide, palladium trifluoroacetate, tetra(triphenylphosphonium tetraphosphonate)palladium, tetra(tri-o-tolylphosphine)palladium, allyl palladium chloride dimer, (1-methylallyl)palladium chloride dimer, allyl(cyclopentadienyl)palladium, bis(tricyclohexylphosphine)palladium, bis(tri-o-tolylphosphine)palladium, tetra(acetonitrile)tetrafluoroborate, palladium benzoate, or 1,2-bis(benzenesulfinyl)ethyl diacetate palladium.

[0016] More preferably, the palladium is palladium acetate, palladium chloride, palladium iodide, or bis(dibenzylacetone)palladium. Or tetra(triphenylphosphine)palladium.

[0017] More preferably, the palladium is tetra(triphenylphosphine)palladium.

[0018] Preferably, the organic solvent is selected from one or more of methanol, ethanol, ethylene glycol, n-propanol, isopropanol, n-butanol, isobutanol, tert-butanol, sec-butanol, tert-pentanol, 4-methyl-2-pentanol, isopentanol, 2-pentanol, diethyl ether, tert-butyl methyl ether, n-butyl ether, isopropyl ether, diphenyl ether, dimethyl sulfide, cyclopentyl methyl ether, anisole, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether, acetonitrile, benzonitrile, toluene, trifluorotoluene, acetone, dichloromethane, 1,2-dichloroethane, dimethyl sulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, N-methylpyrrolidone, ethyl acetate, ethyl formate, propyl formate, 1,4-dioxane, 1,3-dioxane, tetrahydrofuran, 2-methyltetrahydrofuran, or 1,3-dimethyl-2-imidazolinone.

[0019] More preferably, the organic solvent is selected from 1,4-dioxane, methanol, dimethyl sulfoxide, tetrahydrofuran, N,N-diacetamide, toluene, acetonitrile, or ethyl acetate.

[0020] More preferably, the organic solvent is 1,4-dioxane.

[0021] Preferably, the reaction is carried out in an inert gas atmosphere at a temperature of 30–80 °C for 6–36 hours. Beneficial effects

[0022] Compared with existing technologies, this invention provides a method for synthesizing acyclic, non-terminated vicinal diol derivatives based on propargyl esters. It successfully achieves palladium-catalyzed selective alkenylation of propargyl esters with carboxylic acids, constructing a series of trisubstituted acyclic allyl skeletons. This overcomes the limitation of previous alkenylation products to leaving groups, verifies the possibility of different exogenous nucleophiles participating in the selective alkenylation of propargyl esters, and provides valuable experience for transition metal-catalyzed nucleophilic substitution reaction modes of propargyl esters. It has the following advantages: (1) This invention develops a method for synthesizing vicinal diol derivatives by alkenylation of internally aliphatic substituted propargyl esters catalyzed by transition metals: using inexpensive and readily available propargyl esters as reaction substrates, commercially available Pd(PPh3)4 and DPPF as catalysts and ligands, and widely available carboxylic acids and phenols as nucleophiles, a series of acyclic, multi-substituted allyl skeletons are efficiently and simply constructed. (2) The palladium catalyst of this invention is widely available, diverse, and inexpensive. During the reaction, the palladium complexes with organophosphorus ligands, resulting in mild reaction conditions, good functional group compatibility, and direct application to the structural modification of bioactive molecular intermediates. This allows for simultaneous control of the regio, stereo, and chemoselectivity of the reaction, yielding the target product with moderate to good yield and selectivity.

[0023] (3) This invention successfully realized a nucleophilic substitution reaction model using bulk chemicals—carboxylic acids / phenols—as nucleophiles. This expands the application scope of nucleophiles and propargyl esters, provides a new pathway for the selective conversion of propargyl esters catalyzed by transition metals, and provides an important strategy for the late-stage modification of many drug molecules containing carboxyl and phenolic hydroxyl groups.

[0024] (4) This method allows some natural products and bioactive molecules to participate in the reaction as coupling agents, providing an important strategy for the late modification of many drug molecules containing carboxyl and phenolic hydroxyl groups. The reaction conditions are simple, the operation is convenient, the substrate functional groups are compatible and the scope of application is wide, and it has good universal applicability. It also provides a new way for the selective conversion of propargyl esters mediated by transition metals. Detailed Implementation

[0025] The present invention can be better understood from the following embodiments. However, those skilled in the art will readily understand that the descriptions in the embodiments are for illustrative purposes only and should not, and will not, limit the invention as detailed in the claims.

[0026] Unless otherwise specified, the experimental methods described in the examples are conventional methods; unless otherwise specified, the reagents and materials can be obtained commercially or simply prepared using the methods described below.

[0027] Some of the initial substrates were synthesized using the following method. Substrate 2a, substrate 4a, and substrate 5a were synthesized using the method described below.

[0028]

[0029] One part of anhydrous THF (0.5 M) solution of alkyne reagent (1.0 equiv) was placed in a low-temperature reactor at 0°C and stirred. The solution was then slowly added dropwise. nBuLi (2.4 M in THF, 1.0 equiv) was added, and the reaction solution was stirred continuously in a cryogenic reactor at 0°C for 15 minutes. Then, one part of anhydrous THF (1.0 M) solution containing an aldehyde reagent (1.0 equiv) was added dropwise, and the mixture was transferred to room temperature and stirred for 1 hour. Then, one part of anhydrous THF (2.0 M) solution containing Boc2O (2.0 equiv) was slowly added dropwise, and the reaction was carried out at room temperature for 1 hour. Finally, the reaction was quenched with saturated ammonium chloride solution, and the aqueous phase was extracted three times with EtOAc (3 mL). The crude propargyl ester product was obtained by rotary evaporation. Finally, the purified propargyl ester electrophilic reagent was obtained by rapid column chromatography.

[0030] In this embodiment, the reactants for 2a are 1-octyne and o-bromobenzaldehyde; the reactants for 4a are 1-ethynyl-3-fluorobenzene and propionaldehyde; and the reactants for 5a are 5-chloropentyne and p-chlorobenzaldehyde.

[0031]

[0032] Substrate 2a: 1 H NMR (400 MHz, CDCl3) δ 7.77 (dd, J = 7.8, 1.5 Hz, 1H), 7.56 (dd, J= 7.9, 0.8 Hz, 1H), 7.34 (dd, J = 11.0, 4.1 Hz, 1H), 7.20 (td, J = 7.7, 1.6Hz, 1H), 6.52 (t, J = 1.9 Hz, 1H), 2.26 (td, J = 7.1, 2.0 Hz, 2H), 1.56 –1.51 (m, 2H), 1.50 (s, 9H), 1.42 – 1.34 (m, 2H), 1.32 – 1.24 (m, 4H), 0.87(t, J = 6.9 Hz, 3H). 13 C NMR (100 MHz, CDCl3) δ 152.39, 136.75, 133.06,130.40, 129.63, 127.78, 123.47, 89.63, 83.04, 75.74, 68.41, 31.41, 28.61,28.39, 27.90, 22.67, 19.03, 14.19. HRMS (ESI): Calcd 412.1492 for C 20 H 31 BrNO3[M +NH4 + ; Found: 412.1491.

[0033] Substrate 4a: 1 H NMR (400 MHz, CDCl3) δ 7.30 – 7.26 (m, 1H), 7.22 (t, J = 7.3 Hz, 1H), 7.17 – 7.09 (m, 1H), 7.07 – 6.94 (m, 1H), 5.34 (t, J = 6.5 Hz, 1H), 1.97– 1.87 (m, 2H), 1.51 (s, 9H), 1.08 (t, J = 7.4 Hz, 3H). 13 C NMR (100 MHz, CDCl3) δ 163.60, 161.15, 152.83, 130.01, 129.92, 127.89, 127.86, 124.39, 124.30, 118.91, 118.68, 116.17, 115.96, 87.20, 84.64, 82.90, 68.62, 28.34, 27.92, 9.60. 19 F NMR (376 MHz, CDCl3) δ -112.97, 113.01. HRMS (ESI): Calcd for C11H10F [M-OBoc]+ 161.0761; Found: 161.0762.

[0034] Substrate 5a: 1 H NMR (400 MHz, CDCl3) δ 7.56 (d, J = 8.4 Hz, 2H), 7.22 (d, J = 8.3 Hz, 2H), 6.22 (t, J = 1.9 Hz, 1H), 3.63 (t, J = 6.3 Hz, 2H), 2.48 (td, J = 6.9, 2.0 Hz, 2H), 1.99 (p, J = 6.6 Hz, 2H), 1.49 (s, 9H). 13HRMS (ESI): Calcd 360.1127 for C17H24Cl2NO3 [M+NH4]+; Found: 360.1131. In the examples, the organophosphorus ligand L was DPPF, CAS number 12150-46-8, commercially available, with the following specific structural formula: .

[0035] The specific structures of all substrates and products in the embodiments are shown in Table 1.

[0036] Example 1: Synthesis of Compound 1 Add propargyl ester electrophilic reagent compound 1a to a 100 x 16 mm screw-cap reaction tube that has been air-dried and has a magnet. (0.20 mmol, 1.0 equiv) and carboxylic acid nucleophilic compound 1b (0.40 mmol, 2.0 equiv), then sealed with a flap stopper, and transferred to a nitrogen-filled glove box after being purged with nitrogen in a vacuum chamber (3 times). Next, ligands DPPF (6.1 mg, 0.011 mmol, 5.5 mol%), Pd(PPh3)4 (11.6 mg, 0.01 mmol, 5 mol%), and 1,4-dioxane (4.00 mL, 0.05 M) were added sequentially to a screw-top reaction tube, sealed with a screw cap, and transferred out of the glove box. Finally, the reaction tube was placed in a heating module at 50 °C and stirred for 8 hours. The reaction was quenched with saturated ammonium chloride solution, followed by extraction of the aqueous phase three times with EtOAc (3 mL), and then concentrated using a rotary evaporator to obtain the crude product. Finally, product compound 1 (63% yield) was separated by rapid column chromatography (eluent: petroleum ether: ethyl acetate V / V = 45:1). . 1 H NMR (400MHz, CDCl3) δ 7.36 – 7.32 (m, 2H), 7.31 – 7.26 (m, 2H), 7.24 – 7.18 (m, 1H), 6.35 (s, 1H), 5.40 (dd, J =All other spectrum data were in accordance with reported in the literature. Example 2 Synthesis of Compound 2 Add propargyl ester electrophilic reagent compound 1a to a 100 x 16 mm screw-cap reaction tube that has been air-dried and has a magnet. (0.20 mmol, 1.0 equiv) and carboxylic acid nucleophilic compound 2b (0.40 mmol, 2.0 equiv), then sealed with a flap stopper, and transferred to a nitrogen-filled glove box after being purged with nitrogen in a vacuum chamber (3 times). Next, ligands DPPF (6.1 mg, 0.011 mmol, 5.5 mol%), Pd(PPh3)4 (11.6 mg, 0.01 mmol, 5 mol%), and 1,4-dioxane (4.00 mL, 0.05 M) were added sequentially to a screw-top reaction tube, sealed with a screw cap, and transferred out of the glove box. Finally, the reaction tube was placed in a heating module at 50 °C and stirred for 8 hours. The reaction was quenched with saturated ammonium chloride solution, followed by extraction of the aqueous phase three times with EtOAc (3 mL), and then concentrated using a rotary evaporator to obtain the crude product. Finally, product compound 2 (81% yield) was separated by rapid column chromatography (eluent: petroleum ether: ethyl acetate V / V = 100:1). . 1 H NMR (400 MHz, CDCl3) δ 7.41 (d, J = 7.3 Hz, 2H), 7.29 (t, J = 7.5 Hz, 2H), 7.24 –7.18 (m, 1H), 6.25 (s, 1H), 5.41 (dd, J = 7.5, 6.1 Hz, 1H), 1.84 – 1.69 (m,2H), 1.40 (s, 1H), 1.39 – 1.33 (m, 4H), 1.25 (s, 6H), 1.23 (d, J= 2.6 Hz, 6H), 1.21 (s, 1H), 1.19 (s, 3H), 1.17 (s, 3H), 1.15 (s, 3H), 1.10 (s, 3H), 0.91 (t, J = 7.0 Hz, 3H). 13 C NMR (100 MHz, CDCl3) δ 171.33, 169.06, 146.55,134.21, 128.71, 128.41, 127.54, 118.24, 73.35, 36.01, 35.62, 31.78, 31.60,31.56, 30.23, 30.08, 27.60, 23.73, 23.69, 22.59, 16.86, 16.80, 16.55, 16.51,14.13. HRMS (ESI): Calcd 455.3156 for C 29 H 43 O4 [M+H] + Found: 455.3153.

[0037] Example 3 Synthesis of Compound 3 Add propargyl ester electrophilic reagent compound 1a to a 100 x 16 mm screw-cap reaction tube that has been air-dried and has a magnet. (0.20 mmol, 1.0 equiv) and carboxylic acid nucleophilic compound 3b (0.80 mmol, 4.0 equiv), then sealed with a flap stopper, and transferred to a nitrogen-filled glove box after being purged with nitrogen three times in a vacuum chamber. Next, ligands DPPF (6.1 mg, 0.011 mmol, 5.5 mol%), Pd(PPh3)4 (11.6 mg, 0.01 mmol, 5 mol%), and 1,4-dioxane (4.00 mL, 0.05 M) were added sequentially to a screw-cap reaction tube, sealed with a screw cap, and transferred out of the glove box. Finally, the reaction tube was placed in a heating module at 50 °C and stirred for 8 hours. The reaction was quenched with saturated ammonium chloride solution, followed by extraction of the aqueous phase three times with EtOAc (3 mL), and then concentrated using a rotary evaporator to obtain the crude product. Finally, product compound 3 (55% yield) was separated by rapid column chromatography (eluent: petroleum ether: ethyl acetate V / V = 30:1). . 1H NMR (400 MHz, CDCl3) δ 7.26 (s, 5H), 7.15 (d,J = 8.9 Hz, 2H), 7.08 (d, J = 8.8 Hz, 2H), 6.81 (d, J = 8.9 Hz, 2H), 6.68 (d,J = 8.9 Hz, 2H), 6.42 (s, 1H), 5.47 (dd, J = 8.0, 5.9 Hz, 1H), 1.74 – 1.63 (m, 2H), 1.62 (s, 3H), 1.59 (s, 3H), 1.54 (s, 6H), 1.29 – 1.19 (m, 4H), 0.85(t, J = 6.8 Hz, 3H). 13 C NMR (100 MHz, CDCl3) δ 173.22, 170.97, 154.08,153.65, 144.85, 132.86, 129.26, 129.18, 128.81, 128.49, 128.19, HRMS (ESI): Calcd 599.1962 for C 33 H 37 C l2 O6[M+H] + Found: 599.1971. Example 4 Synthesis of Compound 4 Add propargyl ester electrophilic reagent compound 1a to a 100 x 16 mm screw-cap reaction tube that has been air-dried and has a magnet. (0.20 mmol, 1.0 equiv) and carboxylic acid nucleophilic compound 4b (0.80 mmol, 4.0 equiv), then sealed with a flap stopper, and transferred to a nitrogen-filled glove box after being purged with nitrogen three times in a vacuum chamber. Next, ligands DPPF (6.1 mg, 0.011 mmol, 5.5 mol%), Pd(PPh3)4 (11.6 mg, 0.01 mmol, 5 mol%), and 1,4-dioxane (4.00 mL, 0.05 M) were added sequentially to a screw-top reaction tube, sealed with a screw cap, and transferred out of the glove box. Finally, the reaction tube was placed in a heating module at 50 °C and stirred for 8 hours. The reaction was quenched with saturated ammonium chloride solution, followed by extraction of the aqueous phase three times with EtOAc (3 mL), and then concentrated using a rotary evaporator to obtain the crude product. Finally, product compound 4 (36% yield) was separated by rapid column chromatography (eluent: petroleum ether: ethyl acetate V / V = 100:1). . 1 H NMR (400MHz, CDCl3) δ 7.37 – 7.33 (m, 2H), 7.31 – 7.25 (m, 2H), 7.25 – 7.19 (m, 1H), 6.32 (s, 1H), 5.43 (dd, J = 7.7, 6.2 Hz, 1H), 2.69 (dt, J = 14.0, 7.0 Hz, 1H), 2.54 (dt, J = 14.0, 7.0 Hz, 1H), 1.88 – 1.71 (m, 2H), 1.35 (dd, J =11.5, 8.2 Hz, 4H), 1.26 – 1.14 (m, 13H), 0.96 – 0.87 (m, 3H). 13 C NMR (100MHz, CDCl3) δ 176.26, 174.02, 145.64, 133.65, 128.69, 128.44, 127.82, 119.34,73.82, 34.29, 31.71, 27.54, 22.52, 19.16, 19.04, 18.93, 14.11. HRMS (ESI):Calcd 347.2217 for C 21 H 31 O4 [M+H] + Found: 347.2223. Example 5 Synthesis of Compound 5 Add propargyl ester electrophilic reagent compound 1a to a 100 x 16 mm screw-cap reaction tube that has been air-dried and has a magnet. (0.20 mmol, 1.0 equiv) and carboxylic acid nucleophilic compound 5b (0.40 mmol, 2.0 equiv), then sealed with a flap stopper, and transferred to a nitrogen-filled glove box after being purged with nitrogen three times in a vacuum chamber. Next, ligands DPPF (6.1 mg, 0.011 mmol, 5.5 mol%), Pd(PPh3)4 (11.6 mg, 0.01 mmol, 5 mol%), and 1,4-dioxane (4.00 mL, 0.05 M) were added sequentially to a screw-top reaction tube, sealed with a screw cap, and transferred out of the glove box. Finally, the reaction tube was placed in a heating module at 50 °C and stirred for 8 hours. The reaction was quenched with saturated ammonium chloride solution, followed by extraction of the aqueous phase three times with EtOAc (3 mL), and then concentrated using a rotary evaporator to obtain the crude product. Finally, product compound 5 (25% yield) was separated by rapid column chromatography (eluent: petroleum ether: ethyl acetate V / V = 50:1). Z / E = 10 / 1), . 1 H NMR (400 MHz, CDCl3) δ 7.34 (d, J = 7.4 Hz, 2H), 7.31 – 7.26 (m, 2H), 7.21 (t, J = 7.2 Hz, 1H), 6.31 (s, 1H), 5.44 (dd, J =7.7, 6.1 Hz, 1H), 0.91 (t,J = 6.7 Hz, 3H). 13 C NMR (100 MHz, CDCl3) δ 174.63, 172.41, 145.76, 133.67,128.70, 128.45, 127.80, 119.19, 73.82, 38.33, 38.14, 31.73, 27.55, 25.33,25.24, 25.22, 22.51, 18.58, 18.53, 14.09. HRMS (ESI): Calcd 371.2217 forC 23 H 31 O4 [M+H]+ Found: 371.2221. Example 6 Synthesis of Compound 6 Add propargyl ester electrophilic reagent compound 1a to a 100 x 16 mm screw-cap reaction tube that has been air-dried and has a magnet. (0.20 mmol, 1.0 equiv) and carboxylic acid nucleophilic compound 6b (0.40 mmol, 2.0 equiv), then sealed with a flap stopper, and transferred to a nitrogen-filled glove box after being purged with nitrogen three times in a vacuum chamber. Next, ligands DPPF (6.1 mg, 0.011 mmol, 5.5 mol%), Pd(PPh3)4 (11.6 mg, 0.01 mmol, 5 mol%), and 1,4-dioxane (4.00 mL, 0.05 M) were added sequentially to a screw-top reaction tube, sealed with a screw cap, and transferred out of the glove box. Finally, the reaction tube was placed in a heating module at 50 °C and stirred for 8 hours. The reaction was quenched with saturated ammonium chloride solution, followed by extraction of the aqueous phase three times with EtOAc (3 mL), and then concentrated using a rotary evaporator to obtain the crude product. Finally, product compound 6 (69% yield, Z / E = 12 / 1) was separated by rapid column chromatography (eluent: petroleum ether: ethyl acetate V / V = 50:1). . 1 H NMR (400 MHz, CDCl3) δ 7.39 (d, J = 7.4 Hz, 2H), 7.30 (t, J = 7.5 Hz, 2H), 7.26 – 7.21 (m, 1H), 6.29 (s, 1H), 5.44 (dd, J =7.5, 6.1 Hz, 1H), 1.86 – 1.75 (m, 3H), 1.66 – 1.59 (m, 1H), 1.42 – 1.33 (m,4H), 1.07 – 1.00 (m, 4H), 0.96 – 0.90 (m, 4H), 0.90 – 0.76 (m, 3H). 13C NMR(100 MHz, CDCl3) δ 174.02, 171.91, 145.51, 133.56, 128.66, 128.45, 127.80,119.10, 74.05, 31.70, 27.47, 22.50, 14.06, 13.14, 12.99, 8.98, 8.87, 8.59,8.51. HRMS (ESI): Calcd 343.1904 for C 21 H 27 O4 [M+H] + Found: 343.1906. Example 7 Synthesis of Compound 7 Add propargyl ester electrophilic reagent compound 1a to a 100 x 16 mm screw-cap reaction tube that has been air-dried and has a magnet. (0.20 mmol, 1.0 equiv) and carboxylic acid nucleophilic compound 7b (0.40 mmol, 2.0 equiv), then sealed with a flap stopper, and transferred to a nitrogen-filled glove box after being purged with nitrogen three times in a vacuum chamber. Next, ligands DPPF (6.1 mg, 0.011 mmol, 5.5 mol%), Pd(PPh3)4 (11.6 mg, 0.01 mmol, 5 mol%), and 1,4-dioxane (4.00 mL, 0.05 M) were added sequentially to a screw-top reaction tube, sealed with a screw cap, and transferred out of the glove box. Finally, the reaction tube was placed in a heating module at 50 °C and stirred for 8 hours. The reaction was quenched with saturated ammonium chloride solution, followed by extraction of the aqueous phase three times with EtOAc (3 mL), and then concentrated using a rotary evaporator to obtain the crude product. Finally, product compound 7 (55% yield) was separated by rapid column chromatography (eluent: petroleum ether: ethyl acetate V / V = 40:1). . 1H NMR (400MHz, CDCl3) δ 8.13 (dd, J = 8.3, 1.2 Hz, 2H), 8.03 (dd, J = 8.3, 1.3 Hz, 2H), 7.67 – 7.61 (m, 1H), 7.56 – 7.48 (m, 3H), 7.45 – 7.39 (m, 4H), 7.26 – 7.15(m, 3H), 6.51 (s, 1H), 5.86 – 5.79 (m, 1H), 2.06 – 1.94 (m, 2H), 1.53 – 1.44(m, 2H), 1.44 – 1.37 (m, 2H), 0.92 (t, J = 7.2 Hz, 3H).All other spectral data were in accordance with reported in the literature. Example 8 Synthesis of Compound 8 Add propargyl ester electrophilic reagent compound 1a to a 100 x 16 mm screw-cap reaction tube that has been air-dried and has a magnet. (0.20 mmol, 1.0 equiv) and carboxylic acid nucleophilic compound 8b (0.40 mmol, 2.0 equiv), then sealed with a flap stopper, and transferred to a nitrogen-filled glove box after being purged with nitrogen three times in a vacuum chamber. Next, ligands DPPF (6.1 mg, 0.011 mmol, 5.5 mol%), Pd(PPh3)4 (11.6 mg, 0.01 mmol, 5 mol%), and 1,4-dioxane (4.00 mL, 0.05 M) were added sequentially to a screw-top reaction tube, sealed with a screw cap, and transferred out of the glove box. Finally, the reaction tube was placed in a heating module at 50 °C and stirred for 8 hours. The reaction was quenched with saturated ammonium chloride solution, followed by extraction of the aqueous phase three times with EtOAc (3 mL), and then concentrated using a rotary evaporator to obtain the crude product. Finally, product compound 8 (60% yield) was separated by rapid column chromatography (eluent: petroleum ether: ethyl acetate V / V = 50:1). W / E =25 / 1), . 1 H NMR (400 MHz, CDCl3) δ 7.75 (dd, J = 8.2, 1.7 Hz, 1H), 7.65 (dd, J= 8.2, 1.6 Hz, 1H), 7.53 (d, J = 1.6 Hz, 1H), 7.46 (d, J =1.6 Hz, 1H), 7.41 (d, J = 7.2 Hz, 2H), 7.26 – 7.15 (m, 3H), 6.89 (d, J = 8.2Hz, 1H), 6.82 (d, J = 8.2 Hz, 1H), 6.49 (s, 1H), 6.06 (s, 2H), 6.01 (s, 2H), 5.77 (t, J = 6.8 Hz, 1H), 2.03 – 1.92 (m, 2H), 1.54 – 1.37 (m, 4H), 0.93 (t, J = 7.1 Hz, 3H). 13 C NMR (100 MHz, CDCl3) δ 165.11, 163.16, 152.34, 151.68,148.02, 147.72, 145.55, 133.41, 128.65, 128.55, 127.90, 126.32, HRMS (ESI): Calcd 503.1701 for C 29 H 27 O8 [M+H] + Found: 503.1699. Example 9 Synthesis of Compound 9 Add propargyl ester electrophilic reagent compound 1a to a 100 x 16 mm screw-cap reaction tube that has been air-dried and has a magnet. (0.20 mmol, 1.0 equiv) and carboxylic acid nucleophilic compound 9b (0.40 mmol, 2.0 equiv), then sealed with a flap stopper, and transferred to a nitrogen-filled glove box after being purged with nitrogen three times in a vacuum chamber. Next, ligands DPPF (6.1 mg, 0.011 mmol, 5.5 mol%), Pd(PPh3)4 (11.6 mg, 0.01 mmol, 5 mol%), and 1,4-dioxane (4.00 mL, 0.05 M) were added sequentially to a screw-top reaction tube, sealed with a screw cap, and transferred out of the glove box. Finally, the reaction tube was placed in a heating module at 50 °C and stirred for 8 hours. The reaction was quenched with saturated ammonium chloride solution, followed by extraction of the aqueous phase three times with EtOAc (3 mL), and then concentrated using a rotary evaporator to obtain the crude product. Finally, product compound 9 (62% yield) was separated by rapid column chromatography (eluent: petroleum ether: ethyl acetate V / V = 30:1). . 1 H NMR (400 MHz, CDCl3) δ 7.75 (dd, J = 8.2, 1.7 Hz, 1H), 7.65 (dd, J = 8.2, 1.6 Hz, 1H), 7.53 (d, J = 1.6 Hz, 1H), 7.46 (d, J = 1.6 Hz, 1H), 7.41 (d, J = 7.2 Hz,2H), 7.26 – 7.15 (m, 3H), 6.89 (d, J = 8.2 Hz, 1H), 6.82 (d, J = 8.2 Hz, 1H), 6.49 (s, 1H), 6.06 (s, 2H), 6.01 (s, 2H), 5.77 (t, J = 6.8 Hz, 1H), 2.03 –1.92 (m, 2H), 1.54 – 1.37 (m, 4H), 0.93 (t, J = 7.1 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 165.11, 163.16, 152.34, 151.68, 148.02, 147.72, 145.55, 133.41,128.65, 128.55, 127.90, 126.32, HRMS (ESI): Calcd 503.1701 for C 29 H 27 O8 [M+H] + Found: 503.1699. Example 10 Synthesis of Compound 10 Add propargyl ester electrophilic reagent compound 1a to a 100 x 16 mm screw-cap reaction tube that has been air-dried and has a magnet. (0.20 mmol, 1.0 equiv) and carboxylic acid nucleophilic compound 10b (0.40 mmol, 2.0 equiv), then sealed with a flap stopper, and transferred to a nitrogen-filled glove box after being purged with nitrogen three times in a vacuum chamber. Next, ligands DPPF (6.1 mg, 0.011 mmol, 5.5 mol%), Pd(PPh3)4 (11.6 mg, 0.01 mmol, 5 mol%), and 1,4-dioxane (4.00 mL, 0.05 M) were added sequentially to a screw-top reaction tube, sealed with a screw cap, and transferred out of the glove box. Finally, the reaction tube was placed in a heating module at 50 °C and stirred for 8 hours. The reaction was quenched with saturated ammonium chloride solution, followed by extraction of the aqueous phase three times with EtOAc (3 mL), and then concentrated using a rotary evaporator to obtain the crude product. Finally, product compound 10 (50% yield) was separated by rapid column chromatography (eluent: petroleum ether: ethyl acetate V / V = 50:1). . 1 H NMR (400 MHz, CDCl3) δ 7.97 – 7.93 (m, 2H), 7.85 (d, J = 8.6 Hz, 2H), 7.64 (d, J = 8.5 Hz, 2H), 7.55 (d, J= 8.6 Hz, 2H), 7.40 – 7.35 (m, 2H), 7.25 – 7.17 (m,3H), 6.51 (s, 1H), 5.78 (t, J = 6.9 Hz, 1H), 2.04 – 1.92 (m, 2H), 1.50 – 1.36(m, 4H), 0.92 (t, J = 7.1 Hz, 3H). 13 C NMR (100 MHz, CDCl3) δ 165.18, 163.28,145.00, 133.14, 132.24, 131.82, 131.72, 131.38, 129.18, 128.69, 128.27,128.22, 128.17, 120.45, 100.11, 75.23, 31.88, 27.65, 22.55, 14.12. HRMS(ESI): Calcd 571.0114 for C 27 H 25 Br2O4 [M+H] + Found: 571.0111. Example 11 Synthesis of Compound 11 Add propargyl ester electrophilic reagent compound 1a to a 100 x 16 mm screw-cap reaction tube that has been air-dried and has a magnet. (0.20 mmol, 1.0 equiv) and carboxylic acid nucleophilic compound 11b (0.40 mmol, 2.0 equiv), then sealed with a flap stopper, and transferred to a nitrogen-filled glove box after being purged with nitrogen three times in a vacuum chamber. Next, ligands DPPF (6.1 mg, 0.011 mmol, 5.5 mol%), Pd(PPh3)4 (11.6 mg, 0.01 mmol, 5 mol%), and 1,4-dioxane (4.00 mL, 0.05 M) were added sequentially to a screw-cap reaction tube, sealed with a screw cap, and transferred out of the glove box. Finally, the reaction tube was placed in a heating module at 50 °C and stirred for 8 hours. The reaction was quenched with saturated ammonium chloride solution, followed by extraction of the aqueous phase three times with EtOAc (3 mL), and then concentrated using a rotary evaporator to obtain the crude product. Finally, product compound 11 (59% yield) was separated by rapid column chromatography (eluent: petroleum ether: ethyl acetate V / V = 40:1). . 1HNMR (400 MHz, CDCl3) δ 8.09 (d, J = 8.8 Hz, 2H), 8.00 (d, J = 8.8 Hz, 2H), 7.43 (d, J = 7.2 Hz, 2H), 7.24 – 7.11 (m, 3H), 6.97 (d, J = 8.9 Hz, 2H), 6.90(d, J = 8.9 Hz, 2H), 6.50 (s, 1H), 5.81 (t, J = 6.7 Hz, 1H), 3.88 (s, 3H), 3.84 (s, 3H), 2.07 – 1.94 (m, 2H), 1.53 – 1.37 (m, 4H), 0.93 (t, J = 7.1 Hz, 3H). 13 C NMR (100 MHz, CDCl3) δ 165.52, 163.98, 163.53, 163.42, 145.82,133.57, 132.39, 131.88, 128.67, 128.53, 127.81, 122.77, 121.72, 119.38,114.00, 113.64, 74.54, 55.60, 55.50, 32.05, 27.61, 22.57, 14.11. HRMS (ESI): Calcd 475.2115 for C 29 H 31 O6[M+H] + Found: 475.2109. Example 12 Synthesis of Compound 12 Add propargyl ester electrophilic reagent compound 1a to a 100 x 16 mm screw-cap reaction tube that has been air-dried and has a magnet. (0.20 mmol, 1.0 equiv) and carboxylic acid nucleophilic compound 12b (0.40 mmol, 2.0 equiv), then sealed with a flap stopper, and transferred to a nitrogen-filled glove box after being purged with nitrogen three times in a vacuum chamber. Next, ligands DPPF (6.1 mg, 0.011 mmol, 5.5 mol%), Pd(PPh3)4 (11.6 mg, 0.01 mmol, 5 mol%), and 1,4-dioxane (4.00 mL, 0.05 M) were added sequentially to a screw-top reaction tube, sealed with a screw cap, and transferred out of the glove box. Finally, the reaction tube was placed in a heating module at 50 °C and stirred for 8 hours. The reaction was quenched with saturated ammonium chloride solution, followed by extraction of the aqueous phase three times with EtOAc (3 mL), and then concentrated using a rotary evaporator to obtain the crude product. Finally, product compound 12 (72% yield) was separated by rapid column chromatography (eluent: petroleum ether: ethyl acetate V / V = 20:1). . 1 H NMR (400 MHz, CDCl3) δ 7.48 (d, J = 7.5 Hz, 2H), 7.29 (t, J = 7.6 Hz, 2H), 7.20 (t, J = 7.4 Hz, 1H), 6.46 (s, 1H), 5.70 (dd, J = 8.0, 5.5 Hz, 1H), 4.94 – 4.89 (m, 2H), 4.87 – 4.82 (m, 2H), 4.51 – 4.47 (m,2H), 4.43 – 4.40 (m, 2H), 4.28 (s, 5H), 4.24 (s, 5H), 2.03 – 1.87 (m, 2H), 1.55 – 1.40 (m, 4H), 0.96 (t, J = 7.1 Hz, 3H). 13 C NMR (100 MHz, CDCl3) δ170.95, 169.09, 146.52, 133.83, 128.82, 128.58, 127.85, 119.13, 74.09, 71.83,71.44, 71.33, 70.72, 70.68, 70.59, 70.49, 70.36, 70.02, 69.97, 32.44, 27.76,22.71, 14.25. RMS (ESI): Calcd 631.1229 for C 35 H 35Fe2O4[M+H] + Found: 631.1127. Example 13 Synthesis of Compound 13 Add propargyl ester electrophilic reagent compound 1a to a 100 x 16 mm screw-cap reaction tube that has been air-dried and has a magnet. (0.20 mmol, 1.0 equiv) and phenolic nucleophilic compound 13b (0.40 mmol, 2.0 equiv) was then sealed with a flap stopper and transferred to a nitrogen-filled glove box after being purged with nitrogen three times in a vacuum chamber. Next, ligands DPPF (6.1 mg, 0.011 mmol, 5.5 mol%), Pd(PPh3)4 (11.6 mg, 0.01 mmol, 5 mol%), DBU (29.8 μL, 0.20 mmol, 1.0 equiv), and 1,4-dioxane (4.00 mL, 0.05 M) were sequentially added to a screw-cap reaction tube, sealed with a threaded cap, and transferred out of the glove box. Finally, the reaction tube was placed in a heating module at 50 °C and stirred for 8 hours. The reaction was quenched with saturated ammonium chloride solution, followed by extraction of the aqueous phase three times with EtOAc (3 mL), and then concentrated using a rotary evaporator to obtain the crude product. Finally, product compound 13 was obtained by rapid column chromatography (eluent: petroleum ether: ethyl acetate V / V = 100:1) in 68% yield. . 1 H NMR (400 MHz, CDCl3) δ 7.42 (d, J = 7.2Hz, 2H), 7.37 – 7.27 (m, 4H), 7.25 – 7.17 (m, 3H), 6.80 (d, J = 8.9 Hz, 2H), 6.76 (d, J = 8.9 Hz, 2H), 6.31 (s, 1H), 4.60 (dd, J = 7.1, 5.1 Hz, 1H), 1.96– 1.86 (m, 2H), 1.50 – 1.34 (m, 4H), 0.89 (t, J = 7.2 Hz, 3H). 13C NMR (100MHz, CDCl3) δ 157.17, 154.69, 149.37, 133.49, 132.60, 132.43, 128.96, 128.62,127.83, 118.39, 117.93, 117.44, 115.02, 113.65, 78.30, 33.80, 27.62, 22.61,14.13. HRMS (ESI): Calcd 515.0216 for C 25 H 25 Br2O2 [M+H] + Found: 515.0203. Example 14 Synthesis of Compound 14 Add propargyl ester electrophilic reagent compound 1a to a 100 x 16 mm screw-cap reaction tube that has been air-dried and has a magnet. (0.20 mmol, 1.0 equiv) and phenolic nucleophilic compound 13b (0.40 mmol, 2.0 equiv) was then sealed with a flap stopper and transferred to a nitrogen-filled glove box after being purged with nitrogen three times in a vacuum chamber. Next, ligands DPPF (6.1 mg, 0.011 mmol, 5.5 mol%), Pd(PPh3)4 (11.6 mg, 0.01 mmol, 5 mol%), DBU (29.8 μL, 0.20 mmol, 1.0 equiv), and 1,4-dioxane (4.00 mL, 0.05 M) were sequentially added to a screw-cap reaction tube, sealed with a threaded cap, and transferred out of the glove box. Finally, the reaction tube was placed in a heating module at 50 °C and stirred for 8 hours. The reaction was quenched with saturated ammonium chloride solution, followed by extraction of the aqueous phase three times with EtOAc (3 mL), and then concentrated using a rotary evaporator to obtain the crude product. Finally, product compound 14 (68% yield) was obtained by rapid column chromatography (eluent: petroleum ether). . 1H NMR (400 MHz, CDCl3) δ 7.46 (d, 2H), 7.38 – 7.31(m, 2H), 7.26 – 7.20 (m, 2H), 7.18 – 7.12 (m, 1H), 6.12 (s, 1H), 6.08 – 6.00(m, 1H), 5.86 – 5.72 (m, 1H), 2.15 – 2.01 (m, 2H), 1.47 – 1.19 (m, 2H), 0.84(t, J = 7.4 Hz, 3H). 13 C NMR (100 MHz, CDCl3) δ 155.83, 148.72, 134.59,134.20, 132.58, 128.99, 128.62, 127.41, 125.47, 118.62, 117.32, 113.96,34.66, 22.32, 13.74. HRMS (ESI): Calcd 343.0692 for C 19 H 20 BrO [M+H] + Found: 343.0697. Example 15 Synthesis of Compound 15 Add propargyl ester electrophilic reagent compound 1a to a 100 x 16 mm screw-cap reaction tube that has been air-dried and has a magnet. (0.20 mmol, 1.0 equiv) and phenolic nucleophilic compound 14b (0.40 mmol, 2.0 equiv) was then sealed with a flap stopper and transferred to a nitrogen-filled glove box after being purged with nitrogen three times in a vacuum chamber. Next, ligands DPPF (6.1 mg, 0.011 mmol, 5.5 mol%), Pd(PPh3)4 (11.6 mg, 0.01 mmol, 5 mol%), DBU (29.8 μL, 0.20 mmol, 1.0 equiv), and 1,4-dioxane (4.00 mL, 0.05 M) were sequentially added to a screw-cap reaction tube, sealed with a threaded cap, and transferred out of the glove box. Finally, the reaction tube was placed in a heating module at 50 °C and stirred for 8 hours. The reaction was quenched with saturated ammonium chloride solution, followed by extraction of the aqueous phase three times with EtOAc (3 mL), and then concentrated using a rotary evaporator to obtain the crude product. Finally, product compound 15 was obtained by rapid column chromatography (eluent: petroleum ether: ethyl acetate V / V = 60:1) in 60% yield. . 1 H NMR (400 MHz, CDCl3) δ 7.88 (dd, J =30.1, 8.9 Hz, 4H), 7.40 (d, J = 7.0 Hz, 2H), 7.23 – 7.11 (m, 3H), 7.00 – 6.89(m, 4H), 6.38 (s, 1H), 4.86 – 4.77 (m, 1H), 2.93 (dq, J = 14.4, 7.3 Hz, 4H), 2.05 – 1.91 (m, 2H), 1.58 – 1.33 (m, 4H), 1.20 (dt, J = 9.2, 7.3 Hz, 6H), 0.90 (t, J = 7.2 Hz, 3H). 13 C NMR (100 MHz, CDCl3) δ 199.50, 199.46, 161.73,159.38, 148.44, 133.12, 131.68, 130.53, 130.31, 130.28, 128.97, HRMS (ESI): Calcd 471.2530 for C 31 H 34 O4 [M+H] + Found: 471.2537. Example 16 Synthesis of Compound 16 Add propargyl ester electrophilic reagent compound 1a to a 100 x 16 mm screw-cap reaction tube that has been air-dried and has a magnet. (0.20 mmol, 1.0 equiv) and phenolic nucleophilic compound 15b (0.40 mmol, 2.0 equiv), then sealed with a flap stopper, and transferred to a nitrogen-filled glove box after being purged with nitrogen three times through a vacuum chamber. Next, ligands DPPF (6.1 mg, 0.011 mmol, 5.5 mol%), Pd(PPh3)4 (11.6 mg, 0.01 mmol, 5 mol%), DBU (29.8 μL, 0.20 mmol, 1.0 equiv), and 1,4-dioxane (4.00 mL, 0.05 M) were sequentially added to a screw-cap reaction tube, sealed with a threaded cap, and transferred out of the glove box. Finally, the reaction tube was placed in a heating module at 50 °C and stirred for 8 hours. The reaction was quenched with saturated ammonium chloride solution, followed by extraction of the aqueous phase three times with EtOAc (3 mL), and then concentrated using a rotary evaporator to obtain the crude product. Finally, product compound 16 was separated by rapid column chromatography (eluent: petroleum ether: ethyl acetate V / V = 60:1) to obtain product compound 16 (60% yield). . 1 H NMR (400 MHz, CDCl3) δ 7.44 (d, J =7.1 Hz, 2H), 7.39 – 7.30 (m, 2H), 7.28 – 7.17 (m, 3H), 6.48 – 6.33 (m, 5H), 4.71 – 4.64 (m, 1H), 3.80 (s, 3H), 3.63 (s, 3H), 2.03 – 1.88 (m, 2H), 1.55 –1.33 (m, 4H), 0.92 (t, J = 7.2 Hz, 3H). 13 C NMR (100 MHz, CDCl3) δ 158.63,156.75, 156.68, 156.09, 149.17, 133.42, 133.36, 133.09, 128.91, 128.64,127.92, 118.00, HRMS (ESI): Calcd 575.0427 for C 27 H 29 Br2O4[M+H] + Found: 575.0425. Example 17 Synthesis of Compound 17 Add propargyl ester electrophilic reagent compound 1a to a 100 x 16 mm screw-cap reaction tube that has been air-dried and has a magnet. (0.20 mmol, 1.0 equiv) and phenolic nucleophilic compound 16b (0.40 mmol, 2.0 equiv) was then sealed with a flap stopper and transferred to a nitrogen-filled glove box after being purged with nitrogen three times in a vacuum chamber. Next, ligands DPPF (6.1 mg, 0.011 mmol, 5.5 mol%), Pd(PPh3)4 (11.6 mg, 0.01 mmol, 5 mol%), DBU (29.8 μL, 0.20 mmol, 1.0 equiv), and 1,4-dioxane (4.00 mL, 0.05 M) were sequentially added to a screw-cap reaction tube, sealed with a threaded cap, and transferred out of the glove box. Finally, the reaction tube was placed in a heating module at 50 °C and stirred for 8 hours. The reaction was quenched with saturated ammonium chloride solution, followed by extraction of the aqueous phase three times with EtOAc (3 mL), and then concentrated using a rotary evaporator to obtain the crude product. Finally, product compound 17 (77% yield, pdt:iso. = 14:1.7:1, isomers are regioisomers and stereoisomers) was separated by rapid column chromatography (eluent, petroleum ether:ethyl acetate V / V = 100:1). . 1 H NMR (400 MHz, CDCl3) δ 7.56 (dd, J = 7.4, 1.7Hz, 2H), 7.26 (t, J = 7.6 Hz, 2H), 7.20 – 7.15 (m, 1H), 6.95 – 6.90 (m, 2H), 6.88 (d, J = 9.1 Hz, 2H), 6.80 (m, 4H), 6.34 (s, 1H), 4.55 (dd, J = 7.5, 4.4Hz, 1H), 3.78 (d, J = 1.3 Hz, 6H), 1.99 – 1.83 (m, 2H), 1.60 – 1.41 (m, 2H), 1.40 – 1.30 (m, 2H), 0.92 (t, J = 7.2 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ155.29, 154.34, 152.34, 151.56, 149.25, 134.44, 128.85, 128.48, 127.22,118.12, 117.60, 115.45, 114.78, 114.61, 78.30, 55.77, 55.74, 34.30, 27.65,22.64, 14.13. HRMS (ESI): Calcd 419.2217 for C 27 H 31 O4 [M+H] + Found: 419.2220. Example 18 Synthesis of Compound 18 Add propargyl ester electrophilic reagent compound 1a to a 100 x 16 mm screw-cap reaction tube that has been air-dried and has a magnet. (0.20 mmol, 1.0 equiv) and phenolic nucleophilic compound 17b (0.40 mmol, 2.0 equiv) was then sealed with a flap stopper and transferred to a nitrogen-filled glove box after being purged with nitrogen three times in a vacuum chamber. Next, ligands DPPF (6.1 mg, 0.011 mmol, 5.5 mol%), Pd(PPh3)4 (11.6 mg, 0.01 mmol, 5 mol%), DBU (29.8 μL, 0.20 mmol, 1.0 equiv), and 1,4-dioxane (4.00 mL, 0.05 M) were sequentially added to a screw-cap reaction tube, sealed with a threaded cap, and transferred out of the glove box. Finally, the reaction tube was placed in a heating module at 50 °C and stirred for 8 hours. The reaction was quenched with saturated ammonium chloride solution, followed by extraction of the aqueous phase three times with EtOAc (3 mL), and then concentrated using a rotary evaporator to obtain the crude product. Finally, product compound 18 was obtained by rapid column chromatography (eluent: petroleum ether) in 62% yield. . 1 H NMR (400 MHz, CDCl3) δ 7.52 – 7.46 (m, 2H), 7.27 –7.21 (m, 6H), 7.17 – 7.12 (m, 1H), 7.04 – 6.90 (m, 6H), 6.35 (s, 1H), 4.67(dd, J= 7.4, 4.4 Hz, 1H), 2.02 – 1.87 (m, 2H), 1.54 – 1.41 (m, 2H), 1.37 –1.31 (m, 2H), 0.89 (t, J = 7.3 Hz, 3H). 13 C NMR (100 MHz, CDCl3) δ 158.23,155.56, 150.48, 134.16, 129.75, 129.55, 128.91, 128.49, 127.36, 122.73,121.38, 116.96, 116.24, 116.13, 77.41, 34.09, 27.61, 22.66, 14.15. HRMS(ESI): Calcd 367.2268 for C 24 H 31 O3 [M+H] + Found: 367.2275. Example 19 Synthesis of Compound 19 Add propargyl ester electrophilic reagent compound 1a to a 100 x 16 mm screw-cap reaction tube that has been air-dried and has a magnet. (0.20 mmol, 1.0 equiv) and phenolic nucleophilic compound 18b (0.60 mmol, 3.0 equiv), then sealed with a flap stopper, and transferred to a nitrogen-filled glove box after being purged with nitrogen three times in a vacuum chamber. Next, ligands DPPF (6.1 mg, 0.011 mmol, 5.5 mol%), Pd(PPh3)4 (11.6 mg, 0.01 mmol, 5 mol%), DBU (59.6 μL, 0.40 mmol, 2.0 equiv), and 1,4-dioxane (4.00 mL, 0.05 M) were sequentially added to a screw-cap reaction tube, sealed with a threaded cap, and transferred out of the glove box. Finally, the reaction tube was placed in a heating module at 50 °C and stirred for 8 hours. The reaction was quenched with saturated ammonium chloride solution, followed by extraction of the aqueous phase three times with EtOAc (3 mL), and then concentrated using a rotary evaporator to obtain the crude product. Finally, product compound 19 was separated by rapid column chromatography (eluent: petroleum ether: ethyl acetate V / V = 100:1) (56% yield). Z / E = 13 / 1), . 1H NMR (400 MHz, CDCl3) δ7.51 (d, J = 7.7 Hz, 2H), 7.28 – 7.21 (m, 3H), 7.20 – 7.07 (m, 3H), 7.03 –6.90 (m, 2H), 6.90 – 6.80 (m, 3H), 6.39 (s, 1H), 4.74 (t, J = 6.0 Hz, 1H), 2.41 (d, J = 1.8 Hz, 3H), 2.23 (s, 3H), 1.98 (m, 2H), 1.61 – 1.41 (m, 2H), 1.35 (m, 2H), 0.92 (m, 3H). 13 C NMR (100 MHz, CDCl3) δ 156.09, 153.61, 150.72,134.37, 131.31, 130.97, 128.86, 128.49, 127.56, 127.42, 127.31, HRMS (ESI): Calcd 387.2319 for C 27 H 31 O2 [M+H] + Found: 387.2321. Example 20 Synthesis of Compound 20 Add propargyl ester electrophilic reagent compound 2a to a 100 x 16 mm screw-cap reaction tube that has been air-dried and has a magnet. (0.20 mmol, 1.0 equiv) and phenolic nucleophilic compound 19b (0.40 mmol, 2.0 equiv), then sealed with a flap stopper, and transferred to a nitrogen-filled glove box after being purged with nitrogen three times through a vacuum chamber. Next, ligands DPPF (6.1 mg, 0.011 mmol, 5.5 mol%), Pd(PPh3)4 (11.6 mg, 0.01 mmol, 5 mol%), DBU (29.8 μL, 0.20 mmol, 1.0 equiv), and 1,4-dioxane (4.00 mL, 0.05 M) were sequentially added to a screw-cap reaction tube, sealed with a threaded cap, and transferred out of the glove box. Finally, the reaction tube was placed in a heating module at 50 °C and stirred for 8 hours. The reaction was quenched with saturated ammonium chloride solution, followed by extraction of the aqueous phase three times with EtOAc (3 mL), and then concentrated using a rotary evaporator to obtain the crude product. Finally, product compound 20 was obtained by rapid column chromatography (eluent: petroleum ether: ethyl acetate V / V = 100:1) (68% yield). . 1 H NMR (400 MHz, CDCl3) δ 7.77 (m,6H), 7.52 – 7.44 (m, 3H), 7.39 (dt, J = 12.3, 6.3 Hz, 4H), 7.28 – 7.19 (m,3H), 7.06 (m, J = 7.6, 2.3 Hz, 1H), 6.93 (t, J = 7.7 Hz, 1H), 6.87 (d, J =4.7 Hz, 1H), 5.02 (m, 1H), 2.16 (m, 2H), 1.73 – 1.55 (m, 2H), 1.44 (t, J =6.5 Hz, 2H), 1.37 (m, 4H), 0.94 (q, J = 3.7 Hz, 3H). 13C NMR (100 MHz, CDCl3)δ 155.93, 153.48, 151.65, 134.48, 134.16, 133.88, 132.53, 130.28, 129.86,129.78, 129.63, 129.45, 128.69, 127.76, 127.68, 127.23, 127.16, 127.04,126.56, 126.45, 124.46, 124.00, 123.98, 119.85, 118.50, 115.56, 111.43,109.78, 34.40, 31.90, 29.27, 25.57, 22.74, 14.25.HRMS (ESI): Calcd 565.1737for C 35 H 34 BrO2 [M+H] + Found: 565.1744. Example 21 Synthesis of Compound 21 Add propargyl ester electrophilic reagent compound 3a to a 100 x 16 mm screw-cap reaction tube that has been air-dried and has a magnet. (0.20 mmol, 1.0 equiv) and phenolic nucleophilic compound 13b (0.40 mmol, 2.0 equiv) was then sealed with a flap stopper and transferred to a nitrogen-filled glove box after being purged with nitrogen three times in a vacuum chamber. Next, ligands DPPF (6.1 mg, 0.011 mmol, 5.5 mol%), Pd(PPh3)4 (11.6 mg, 0.01 mmol, 5 mol%), DBU (29.8 μL, 0.20 mmol, 1.0 equiv), and 1,4-dioxane (4.00 mL, 0.05 M) were sequentially added to a screw-cap reaction tube, sealed with a threaded cap, and transferred out of the glove box. Finally, the reaction tube was placed in a heating module at 50 °C and stirred for 8 hours. The reaction was quenched with saturated ammonium chloride solution, followed by extraction of the aqueous phase three times with EtOAc (3 mL), and then concentrated using a rotary evaporator to obtain the crude product. Finally, product compound 21 was separated by rapid column chromatography (eluent: petroleum ether: ethyl acetate V / V = 100:1) to obtain product compound 21 (57% yield). . 1H NMR (400 MHz, CDCl3) δ 7.47 – 7.42 (m,2H), 7.38 – 7.31 (m, 4H), 7.26 – 7.16 (m, 3H), 6.89 – 6.82 (m, 2H), 6.82 –6.73 (m, 2H), 4.84 – 4.75 (m, 1H), 1.58 (d, J = 6.4 Hz, 3H). 13 C NMR (100 MHz, CDCl3) δ 156.71, 154.73, 150.28, 133.45, 132.65, 132.46, 128.99, 128.62,127.87, 118.33, 117.98, 116.82, 115.03, 113.75, 74.13, 20.09. HRMS (ESI):Calcd 472.9747 for C 22 H 19 Br2O2 [M+H] + Found: 472.9744. Example 22 Synthesis of Compound 22 Add propargyl ester electrophilic reagent compound 4a to a 100 x 16 mm screw-cap reaction tube that has been air-dried and has a magnet. (0.20 mmol, 1.0 equiv) and phenolic nucleophilic compound 13b (0.40 mmol, 2.0 equiv) was then sealed with a flap stopper and transferred to a nitrogen-filled glove box after being purged with nitrogen three times in a vacuum chamber. Next, ligands DPPF (6.1 mg, 0.011 mmol, 5.5 mol%), Pd(PPh3)4 (11.6 mg, 0.01 mmol, 5 mol%), DBU (29.8 μL, 0.20 mmol, 1.0 equiv), and 1,4-dioxane (4.00 mL, 0.05 M) were sequentially added to a screw-cap reaction tube, sealed with a threaded cap, and transferred out of the glove box. Finally, the reaction tube was placed in a heating module at 50 °C and stirred for 8 hours. The reaction was quenched with saturated ammonium chloride solution, followed by extraction of the aqueous phase three times with EtOAc (3 mL), and then concentrated using a rotary evaporator to obtain the crude product. Finally, product compound 22 was separated by rapid column chromatography (eluent: petroleum ether: ethyl acetate V / V = 100:1) to obtain product compound 22 (65% yield). . 1H NMR (400 MHz, CDCl3) δ 7.38 (s, 1H), 7.38 –7.32 (m, 2H), 7.33 (s, 1H), 6.88 (m, 1H), 6.80 (dd, J = 17.6, 8.9 Hz, 4H), 6.31 (s, 1H), 4.57 (dd, J = 7.0, 4.8 Hz, 1H), 2.06 – 1.82 (m, 2H), 1.05 (t, J = 7.4 Hz, 3H). 19 F NMR (376 MHz, CDCl3) δ -112.99. 13 C NMR (100 MHz, CDCl3) δ164.07, 161.63, 157.07, 154.42, 150.43, δ 135.61 (d, J = 8.2 Hz), 133.86 (d, J = 19.4 Hz), 132.74, 132.49,129.95 (d, J = 8.4 Hz), 128.83, 128.62 (d, J =6.9 Hz), 124.79, 124.76, 118.42, 117.93, 116.26 (d, J = 2.6 Hz), 115.61,115.39, 114.78, 114.57, 78.94, 27.04, 9.73. HRMS (ESI): Calcd 504.9809 forC 23 H 20 Br2FO2 [M+H] + Found: 504.9811. Example 23 Synthesis of Compound 23 Add propargyl ester electrophilic reagent compound 5a to a 100 x 16 mm screw-cap reaction tube that has been air-dried and has a magnet. (0.20 mmol, 1.0 equiv) and phenolic nucleophilic compound 13b (0.40 mmol, 2.0 equiv), then sealed with a flap stopper, and transferred to a nitrogen-filled glove box after being purged with nitrogen three times in a vacuum chamber. Next, ligands DPPF (6.1 mg, 0.011 mmol, 5.5 mol%), Pd(PPh3)4 (11.6 mg, 0.01 mmol, 5 mol%), DBU (29.8 μL, 0.20 mmol, 1.0 equiv), and 1,4-dioxane (4.00 mL, 0.05 M) were sequentially added to a screw-cap reaction tube, sealed with a threaded cap, and transferred out of the glove box. Finally, the reaction tube was placed in a heating module at 50 °C and stirred for 8 hours. The reaction was quenched with saturated ammonium chloride solution, followed by extraction of the aqueous phase three times with EtOAc (3 mL), and then concentrated using a rotary evaporator to obtain the crude product. Finally, product compound 23 was separated by rapid column chromatography (eluent: petroleum ether: ethyl acetate V / V = 100:1) to obtain product compound 23 (65% yield). . 1 H NMR (400 MHz, CDCl3) δ7.57 (dd, J = 7.5, 2.0 Hz, 1H), 7.48 – 7.35 (m, 2H), 7.33 – 7.22 (m, 3H), 7.06 (m, J = 16.3, 7.4, 1.8 Hz, 2H), 6.92 – 6.80 (m, 2H), 6.75 – 6.69 (m,2H), 6.66 (s, 1H), 4.73 (dd, J = 6.9, 4.4 Hz, 1H), 3.61 (t, J = 6.2 Hz, 2H), 2.23 – 2.05 (m, 3H), 2.01 (m, 1H). 13 C NMR (100 MHz, CDCl3) δ 156.79, 154.57,150.36, 133.27, 132.51, 131.42, 130.16, 129.40, 128.92, 126.74, 118.18,118.08, 115.14, 114.10, 113.41, 77.52, 44.78, 31.24, 28.45. HRMS (ESI): Calcd568.9280 for C 24 H 21 Br2Cl2O2[M+H] + Found: 568.9268. Comparative Example 1 Comparative Example 1 uses the same method as Example 1, except that no palladium catalyst is added and the yield of the target product is 0.

[0038] Comparative Example 2 Comparative Example 2 uses the same method as Example 1, except that no exogenous alkali potassium methoxide is added, resulting in a low yield of the target product.

[0039] Comparative Example 3 Comparative Example 3 uses the same method as Example 1, except that replacing the ligand DPPF with other ligands, such as BINAP or DPPE, does not yield the target product.

[0040] The above description is merely a preferred embodiment of the present invention and is not intended to limit the invention in any way. Although the present invention has been disclosed above with reference to preferred embodiments, it is not intended to limit the invention. The various palladium catalysts in the present invention can theoretically undergo oxidative addition with propargyl esters, thereby facilitating the smooth progress of the reaction. Modification of substituents only affects the reaction to a certain extent and does not play a decisive role in the occurrence of the reaction. Anyone skilled in the art will readily understand that, without departing from the scope of the present invention, variations 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 to achieve the method of the present invention. Any modifications, alterations, or equivalent changes made to the above embodiments based on the present invention without departing from the spirit of the present invention are still within the scope of the present invention.

Claims

1. A method for synthesizing acyclic, non-terminated vicinal diol derivatives based on propargyl esters, characterized in that, In a solvent, propargyl ester and carboxylic acid / phenol nucleophiles or Using palladium as the reaction substrate, a catalytic system of transition metal and organophosphorus ligand ligand was employed in a base environment. After the reaction was completed, the acyclic, non-terminated vicinal diol derivative was obtained. or Wherein: the molar ratio of propargyl ester, carboxylic acid / phenol, transition metal palladium, and base is 1:(1-2):(0.01-0.2):(1-5); R 1 R 2 With R 4 R indicates alkyl or aryl. 3 It represents an aryl group.

2. The method for synthesizing acyclic, non-terminated vicinal diol derivatives based on propargyl esters according to claim 1, characterized in that, The substituents of the alkyl group are each independently selected from C1 to C20 alkyl, C1 to C20 haloalkyl, C1 to C20 alkylcarbonyl, nitro, hydroxyl, ester, alkenyl, ether, amide, silyl, mercapto, amino, or cyano; the aryl group represents a benzene ring substituted or unsubstituted with biphenyl, naphthyl, anthracene, or a heteroaryl group containing N, O, or S of five to thirteen rings.

3. The method for synthesizing acyclic, non-terminated vicinal diol derivatives based on propargyl esters according to claim 1, characterized in that, The carboxylic acid / phenol nucleophile is selected from one or more of alkyl carboxylic acids / phenol, aryl carboxylic acids / phenol, amino carboxylic acids / phenol, alkoxy carboxylic acids / phenol, aryloxy carboxylic acids / phenol, and arylalkyl carboxylic acids / phenol.

4. The method for synthesizing acyclic, non-terminated vicinal diol derivatives based on propargyl esters according to claim 1, characterized in that, The organophosphine ligand is a bidentate N ligand, a bidentate P ligand, a bidentate NP ligand, a monodentate N ligand, a monodentate phosphine ligand, a tridentate NPN ligand, a tridentate NSP ligand, or a tridentate N ligand.

5. The method for synthesizing acyclic, non-terminated vicinal diol derivatives based on propargyl esters according to claim 4, characterized in that, The organophosphine ligand is an oxazoline ligand, a diamine ligand, a monodentate phosphine ligand, a phosphoramide ligand, a biphenyl bidentate phosphine ligand, a spirocyclic bidentate phosphine ligand, a binatate bidentate phosphine ligand, or a sulfinamide-substituted phosphine ligand.

6. The method for synthesizing acyclic, non-terminated vicinal diol derivatives based on propargyl esters according to claim 5, characterized in that, The organophosphine ligand is a biphenyl bidentate phosphine ligand, a chain bidentate phosphine ligand, a binatane bidentate phosphine ligand, or a bidentate phosphine ligand with a ferrocene framework.

7. The method for synthesizing acyclic, non-terminated vicinal diol derivatives based on propargyl esters according to claim 1, characterized in that, The base is selected from one or more of sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium methoxide, potassium ethoxide, potassium tert-butoxide, sodium tert-pentoxide, potassium tert-pentoxide, sodium borohydride, sodium cyanoborohydride, lithium aluminum hydride, potassium carbonate, sodium carbonate, cesium carbonate, potassium phosphate, triethylamine, DBU (1,8-diazobicyclo[5.4.0]undecyl-7-ene), triethylenediamine, TBD (1,5,7-triazidobicyclo(4.4.0)decyl-5-ene), and tetramethylguanidine.

8. The method for synthesizing acyclic, non-terminated vicinal diol derivatives based on propargyl esters according to claim 1, characterized in that, The palladium is selected from palladium chloride, palladium bromide, palladium iodide, palladium acetate, palladium neopentanoate, bis(triphenylphosphine)acetate, 1,2-bis(diphenylphosphine)ethane palladium chloride, (1,1'-bis(diphenylphosphine)ferrocene)dichloride palladium, acetylacetone palladium, bis(hexafluoroacetylacetone)palladium, bis(triphenylphosphine)dichloride palladium, tetra(triphenylphosphine)palladium, bis(tri-tert-butylphosphine)palladium, bis(dibenzylacetone)palladium, chloro(crotonyl)(tricyclohexylphosphine)palladium, tri(dibenzylacetone)di... One or more of palladium, tris(dibenzylacetone)dipalladium-chloroform adduct, (1,5-cyclooctadiene)palladium dibromide, palladium trifluoroacetate, tetra(triphenyl phosphonite)palladium, tetra(tri-o-tolylphosphine)palladium, allyl palladium chloride dimer, (1-methylallyl)palladium chloride dimer, allyl(cyclopentadienyl)palladium, bis(tricyclohexylphosphine)palladium, bis(tri-o-tolylphosphine)palladium, tetra(acetonitrile)tetrafluoroborate, palladium benzoate, or 1,2-bis(benzenesulfinyl)ethyl diacetate palladium.

9. The method for synthesizing acyclic, non-terminated vicinal diol derivatives based on propargyl esters according to claim 1, characterized in that, The organic solvent is selected from one or more of methanol, ethanol, ethylene glycol, n-propanol, isopropanol, n-butanol, isobutanol, tert-butanol, sec-butanol, tert-pentanol, 4-methyl-2-pentanol, isopentanol, 2-pentanol, diethyl ether, tert-butyl methyl ether, n-butyl ether, isopropyl ether, diphenyl ether, dimethyl sulfide, cyclopentyl methyl ether, anisole, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether, acetonitrile, benzonitrile, toluene, trifluorotoluene, acetone, dichloromethane, 1,2-dichloroethane, dimethyl sulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, N-methylpyrrolidone, ethyl acetate, ethyl formate, propyl formate, 1,4-dioxane, 1,3-dioxane, tetrahydrofuran, 2-methyltetrahydrofuran, or 1,3-dimethyl-2-imidazolinone.

10. The method for synthesizing acyclic, non-terminated vicinal diol derivatives based on propargyl esters according to claim 1, characterized in that, The reaction is carried out in an inert gas atmosphere at a temperature of 30–80 °C for 8–36 hours.

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