Preparation method of aryl terminal alkyne

Abstract

The invention discloses a preparation method of aryl terminal alkyne, which comprises the following steps: carrying out coupling reaction on aryl chloride with a specific structure and silicon acetylene under the synergistic catalysis of a Pd procatalyst and a phosphine ligand, and carrying out subsequent desilicification to finally prepare the aryl terminal alkyne. The raw material chlorinated aromatic hydrocarbon used in the method is cheap and easy to obtain, the dosage of the required Pd procatalyst is low, the production cost can be reduced, in addition, the Pd procatalyst with a specific structure and the phosphine ligand with a specific structure can efficiently play a synergistic catalysis role, and the catalytic efficiency and the product yield are effectively improved.

Description

Technical Field

[0001] The present application relates to the technical field of chemical synthesis, and particularly to a method for preparing aryl terminal alkynes. Background Art

[0002] Terminal alkynes are a class of alkyne compounds containing terminal triple bonds, and their structural feature is that at least one triple-bonded carbon atom in the carbon-carbon triple bond (C≡C) is connected to a hydrogen atom. Terminal alkynes are an important fine chemical raw material and are widely used in fields such as medicine, pesticides, and materials.

[0003] The Corey-Fucks reaction is a commonly used method for preparing terminal alkynes. It uses n-BuLi (n-butyllithium) as a base and reducing agent to react with 1,1-gem-dibromoolefin compounds at -78 °C to obtain alkynyllithium, which is hydrolyzed to obtain terminal alkynes. However, the application of n-BuLi has too many restrictions on the functional groups of the reactants. For example, substrates containing halogenated groups, hydroxyl groups, amino groups, cyano groups, ester groups, carbonyl groups, etc. are not suitable. Moreover, the reaction conditions are harsh, requiring anhydrous and anaerobic conditions, and the operation is relatively cumbersome. A series of subsequent improvements to the Corey-Fucks reaction mainly optimize the base used in the reaction. For example, using Grignard reagents, LiHMDS, NaHMDS, t-BuOK, etc. instead of n-BuLi can also obtain terminal alkynes, but still require anhydrous and low-temperature operations, and the substrate applicability is also limited. The improved reactions of Ohira and Bestmann et al. on Seyferth-Gilbert Homologationfa are also commonly used methods for preparing terminal alkynes. This method can obtain terminal alkynes by reacting aldehydes with Bestmann-Ohira reagents under the action of a weak base K2CO3 at room temperature (S. Ohira. Synth. Commun. 1989, 19, 561-564; H. J. Bestmann, et al. Synlett. 1996, 521–522.). However, the phosphorus reagent used in this method is expensive, and this method cannot prepare conjugated enyne compounds.

[0004] In summary, the methods for preparing terminal alkynes in the prior art are limited by relatively harsh reaction conditions, poor functional group compatibility, or high difficulty in obtaining reagents, etc., and are not suitable for the large-scale production of terminal alkynes. Summary of the Invention

[0005] To overcome the deficiencies of the prior art, the present invention provides a method for preparing aryl terminal alkynes.

[0006] One aspect of the present application discloses a method for preparing aryl terminal alkynes, and the preparation method includes the following steps (1) and (2):

[0007] (1)

[0008] (2)

[0009] Among them, R1, R2, and R3 are each independently selected from: -H, C1-C 10 alkyl group.

[0010] Ar is selected from one of the following structures:

[0011] Among them, X is CH or N.

[0012] R A is selected from: -H, -CN, -CO-(C6-C 10 aryl).

[0013] R J and R K are each independently selected from: -H, C1-C 10 alkyl group.

[0014] R B is selected from: -H, -(C0-C 10 alkylene)-NH2, -(C0-C 10 alkylene)-CO-(C1-C 10 alkyl), -(C0-C 10 alkylene)-CN, -(C0-C 10 alkylene)-(C6-C 10 aryl), -(C0-C 10 alkylene)-NO2.

[0015] R C is selected from: -H, -(C0-C 10 alkylene)-COO(C1-C 10 alkyl).

[0016] R D is selected from: -H, C1-C 10 alkyl group.

[0017] Y is CH or N.

[0018] Z is CH or N.

[0019] R E , R F , R G , R H , R I are each independently selected from: -H, C1-C 10 alkyl group.

[0020] The precatalyst contains at least one of the following structures:

[0021]

[0022] The ligand includes at least one of the following structures:

[0023]

[0024] In this application, terminal alkynes are prepared using inexpensive and easily accessible chloroarenes, coupled with silylacetylene under the catalysis of a palladium catalyst, and terminal alkynes are prepared through subsequent desilylation. The amount of the palladium catalyst required can be relatively low, and the synthesis method is simple, easy to operate, has good catalytic efficiency and good yield, providing a new and large-scale production-friendly scheme for the synthesis of terminal alkynes.

[0025] In one implementation of this application, R1, R2, and R3 are each independently C 1-10 alkyl. For example, R1, R2, and R3 can each independently be an alkyl group with 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms. Preferably, R1, R2, and R3 are each independently C3 alkyl (i.e., trialkyl). More preferably, R1, R2, and R3 are each independently isopropyl.

[0026] In one implementation of this application, R A is selected from: -H, -CN, -CO-(C 6-8 aryl).

[0027] In one implementation of this application, R A is selected from: -H, -CN, -CO-phenyl.

[0028] In one implementation of this application, R J is -H.

[0029] In one implementation of this application, R K is C1-C 10 alkyl.

[0030] In one implementation of this application, R B is selected from: -H, -NH2, -CO-(C1-C 10 alkyl), -CN, -(C 6-8 aryl), -NO2, preferably -H, -NH2, -CO-CH3, -CN, -phenyl, -NO2.

[0031] In one implementation of this application, R C is selected from: -H, -COO(C1-C 10 alkyl), preferably R CSelected from: -H, -COOCH3.

[0032] In one implementation of the present application, R D is -H.

[0033] In one implementation of the present application, R E , R F , R G , R H , R I are each independently -H.

[0034] In one implementation of the present application, the amount of the precatalyst is 0.0001 - 0.001 molar equivalents of the compound shown in Structural Formula I. For example, the amount of the precatalyst can be 0.0001, 0.0002, 0.0003, 0.0004, 0.0005, 0.0006, 0.0007, 0.0008, 0.0009, or 0.001 molar equivalents of the compound shown in Structural Formula I. Preferably, the amount of the precatalyst is 0.0008 molar equivalents of the compound shown in Structural Formula I.

[0035] In one implementation of the present application, the amount of the ligand is 0.01 - 0.1 molar equivalents of the compound shown in Structural Formula I. For example, the amount of the ligand can be 0.01, 0.02, 0.03,

[0036] 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, or 0.1 molar equivalents of the compound shown in Structural Formula I. Preferably, the amount of the ligand is 0.05 molar equivalents of the compound shown in Structural Formula I.

[0037] In one implementation of the present application, the structure of the compound of Formula I is at least one of I-1 to I-12:

[0038]

[0039] In one implementation of the present application, the structure of the compound of Formula II is at least one of II-1 to II-12:

[0040]

[0041] In one implementation of the present application, the basic reagent is selected from at least one of potassium carbonate, cesium carbonate, and potassium phosphate.

[0042] In one implementation of the present application, the addition amount of the basic reagent is 1.0 - 3.0 molar equivalents of the compound shown in Structural Formula I. For example, the addition amount of the basic reagent can be 1.0, 1.5, 2.0, 2.5, or 3.0 molar equivalents of the compound shown in Structural Formula I.

[0043] In one implementation of the present application, the first solvent is a benzene solvent or an ether solvent, preferably a benzene solvent.

[0044] In one implementation of the present application, the first solvent is selected from at least one of toluene, o-xylene, and mesitylene.

[0045] In one implementation of the present application, the second solvent is selected from one of tetrahydrofuran, ethyl acetate, dichloromethane, and methanol. Preferably, it is tetrahydrofuran.

[0046] In one implementation of the present application, the fluoride salt is selected from one of tetrabutylammonium fluoride, potassium fluoride, and cesium fluoride.

[0047] In one implementation of the present application, the addition amount of the fluoride salt is 1.0 - 10.0 molar equivalents of the compound shown in Structural Formula I. For example, the addition amount of the fluoride salt can be 1.0, 2.0, 3.0, 4.0, 5.0, 6.0, 7.0, 8.0, 9.0, or 10.0 molar equivalents of the compound shown in Structural Formula I.

[0048] In one implementation of the present application, the fluoride salt is tetrabutylammonium fluoride. The addition amount of tetrabutylammonium fluoride is 3.0 molar equivalents of the compound shown in Structural Formula I.

[0049] In one implementation of the present application, the reaction temperature in step (1) is 20°C - 200°C. For example, the reaction temperature in step (1) can be 20°C, 40°C, 60°C, 80°C, 100°C, 120°C, 140°C, 160°C, 180°C, or 200°C.

[0050] In one implementation of the present application, the reaction time in step (1) is 5h - 15h. For example, the reaction time in step (1) can be 5h, 8h, 10h, 12h, or 15h.

[0051] In one implementation of the present application, the reaction temperature in step (2) is 20°C - 30°C. For example, the reaction temperature in step (2) can be 20°C, 21°C, 22°C, 23°C, 24°C, 25°C, 26°C, 27°C, 28°C, 29°C, or 30°C.

[0052] In one implementation of the present application, the reaction time in step (2) is 1h - 10h. For example, the reaction time in step (2) can be 1h, 3h, 5h, 8h, or 10h.

[0053] In one implementation of the present application, both step (1) and step (2) are carried out in an anaerobic environment.

[0054] In one implementation of the present application, the anaerobic environment is an inert gas atmosphere. It should be noted that introducing an inert gas into the reaction system in the present application is mainly to create an anaerobic environment. If an anaerobic environment can be ensured, the inert gas may not be used.

[0055] In one implementation of the present application, the inert gas is at least one of nitrogen, helium, neon, argon, krypton, and xenon.

[0056] In one implementation of the present application, the inert gas is nitrogen.

[0057] The beneficial effects of the present application are as follows:

[0058] In the present application, inexpensive and easily obtainable chloroarenes are used to prepare terminal alkynes, which are coupled with silylacetylene under the catalysis of a palladium catalyst, and terminal alkynes are prepared through subsequent desilylation. The amount of the required palladium catalyst can be relatively low, and the synthesis method is simple, easy to operate, has good catalytic efficiency and good yield, providing a new and large-scale production-friendly scheme for the synthesis of terminal alkynes. Description of the Drawings

[0059] Figure 1 is the nuclear magnetic resonance hydrogen spectrum of the terminal alkyne shown in II-1 in the embodiment of the present application.

[0060] Figure 2 is the nuclear magnetic resonance carbon spectrum of the terminal alkyne shown in II-1 in the embodiment of the present application.

[0061] Figure 3 is the nuclear magnetic resonance hydrogen spectrum of the terminal alkyne shown in II-2 in the embodiment of the present application.

[0062] Figure 4 is the nuclear magnetic resonance carbon spectrum of the terminal alkyne shown in II-2 in the embodiment of the present application.

[0063] Figure 5 is the nuclear magnetic resonance hydrogen spectrum of the terminal alkyne shown in II-3 in the embodiment of the present application.

[0064] Figure 6 is the nuclear magnetic resonance carbon spectrum of the terminal alkyne shown in II-3 in the embodiment of the present application.

[0065] Figure 7 is the nuclear magnetic resonance hydrogen spectrum of the terminal alkyne shown in II-4 in the embodiment of the present application.

[0066] Figure 8 is the nuclear magnetic resonance carbon spectrum of the terminal alkyne shown in II-4 in the embodiment of the present application.

[0067] Figure 9 is the nuclear magnetic resonance hydrogen spectrum of the terminal alkyne shown in II-5 in the embodiment of the present application.

[0068] Figure 10 It is the nuclear magnetic resonance carbon spectrum of the terminal alkyne shown in II-5 in the embodiments of the present application.

[0069] Figure 11 It is the nuclear magnetic resonance hydrogen spectrum of the terminal alkyne shown in II-6 in the embodiments of the present application.

[0070] Figure 12 It is the nuclear magnetic resonance carbon spectrum of the terminal alkyne shown in II-6 in the embodiments of the present application. Detailed Embodiments

[0071] The present invention will be further described in detail below in conjunction with the accompanying drawings through specific embodiments. In the following embodiments, many details are described to enable a better understanding of the present application. However, those skilled in the art can easily recognize that some of the features can be omitted in different situations, or can be replaced by other materials or methods. In some cases, some operations related to the present application are not shown or described in the specification, which is to avoid the core part of the present application being overwhelmed by excessive description. For those skilled in the art, it is not necessary to describe these related operations in detail, and they can fully understand the related operations based on the description in the specification and the general technical knowledge in the art.

[0072] In addition, the features, operations or characteristics described in the specification can be combined in any suitable manner to form various embodiments. At the same time, the steps or actions in the method description can also be reordered or adjusted in an obvious manner by those skilled in the art. Therefore, the various sequences in the specification and the drawings are only for clearly describing a certain embodiment, and do not mean that they are necessary sequences, unless it is stated that a certain sequence must be followed.

[0073] In the present application, for example, "Structural Formula I", "Structural Formula II", etc. are only used to distinguish the described objects and do not have any sequential or technical meaning. In the present application, the description of a numerical range includes the endpoints and any value within the range. For example, "1-10" can include 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10.

[0074] Unless otherwise defined, all scientific and technical terms used in the present invention have the same meaning as commonly understood by those skilled in the technical field related to the present invention.

[0075] The term "alkyl" refers to a straight-chain or branched-chain hydrocarbon chain radical that does not contain an unsaturated bond, and the hydrocarbon chain radical is connected to other parts of the molecule by a single bond. Typical alkyl groups contain 1 to 10 (for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10) carbon atoms, that is, C 1-10 alkyl or C1-C 10Alkyl; preferably containing 1 to 6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, n-hexyl, isohexyl, etc.

[0076] The term "alkylene" refers to a hydrocarbon group (divalent alkyl) formed by removing two hydrogen atoms from an alkane molecule, which can be straight-chain or branched and is connected to other parts of the molecule by a single bond. In this article, typical alkylene contains 1 to 10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10) carbon atoms, preferably containing 1 to 6 carbon atoms, such as methylene (-CH2-), ethylene, propylene, butylene, etc. In the present invention, C0 alkylene refers to a single bond, that is, C 0-10 Alkylene (or C0-C 10 Alkylene) includes a single bond and C 1-10 Alkylene (or C1-C10 alkylene).

[0077] The term "aryl" refers to a monocyclic or polycyclic radical, including polycyclic radicals containing monocyclic aryl groups and / or fused aryl groups, such as containing 1-3 monocyclic or fused rings and 6-18 (e.g., 6, 8, 10, 12, 14, 16, 18) carbon ring atoms. The C 6-10 aryl or C6-C 10 aryl in the present invention refers to an aryl containing 6-10 carbon ring atoms, such as phenyl, naphthyl, biphenyl, indenyl, etc.

[0078] The term "pre-catalyst" or "precursor catalyst" refers to a Pre-catalyst, which is an intermediate or precursor substance that usually needs to undergo activation or other transformation steps before the actual catalytic reaction starts to become a truly catalytically active substance.

[0079] The term "TIPs" refers to Triisopropylsilyl (trisopropylsilyl), which is usually a protecting group or modifying group with the chemical formula (i-Pr)3Si-, where i-Pr represents isopropyl (-CH(CH3)2).

[0080] In this application, the term "o-xylene" is o-xylene.

[0081] In this application, the term "Cs2CO3" is cesium carbonate.

[0082] In this application, the term "K2CO3" is potassium carbonate.

[0083] In this application, the term "KOH" is potassium hydroxide.

[0084] In this application, the term "DBN" is 1,5-diazabicyclo[4.3.0]non-5-ene, and the structural formula is

[0085] In this application, the term "DMAP" refers to 4-dimethylaminopyridine, and its structural formula is

[0086] In this application, the term "DABCO" refers to triethylenediamine.

[0087] In this application, the term "DMF" refers to N,N-dimethylformamide.

[0088] In this application, the term "DMSO" refers to dimethyl sulfoxide.

[0089] In this application, the term "NMP" refers to N-methylpyrrolidone.

[0090] In this application, the term "MeCN" refers to acetonitrile.

[0091] In this application, the term "DCE" refers to 1,2-dichloroethane.

[0092] In this application, the term "KF" refers to potassium fluoride.

[0093] In this application, the term "CsF" refers to cesium fluoride.

[0094] In this application, the term "TBAF" refers to tetrabutylammonium fluoride.

[0095] In this application, the term "EA" refers to ethyl acetate.

[0096] In this application, the term "DCM" refers to dichloromethane.

[0097] In this application, the term "MeOH" refers to methanol.

[0098] Terminal alkynes are not only common synthetic units but also widely present in drugs and natural products. For example, enuracil (an anticancer drug), erlotinib (an anticancer drug), and ethisterone (a progestogen) all contain terminal alkynyl groups. Although terminal alkynes have extensive applications in organic chemistry, their synthetic methods are relatively limited. The α,β-elimination of ortho-halides is a classical method for synthesizing terminal alkynes. In addition, the Seyferth-Gilbert reaction and the Corey-Fuchs reaction are also common methods for synthesizing terminal alkynes (starting from aldehydes). However, these methods are limited by harsh reaction conditions (requiring stoichiometric amounts of strong base) and poor functional group compatibility, and are not suitable for the large-scale production of terminal alkynes. A mild method for preparing terminal alkynes involves the Sonogashira coupling of (trialkylsilyl)acetylene with aryl halides followed by desilylation. Methods for preparing terminal alkynes through the Sonogashira reaction using bromoarenes or iodoarenes have been developed. However, examples using inexpensive chloroarenes are relatively limited. In addition, the equivalent amount of palladium catalyst used in such reactions is usually in the range of 1 - 10 mol% (1 mole percentage to 10 mole percentages), which accounts for a considerable cost and may cause harmful environmental effects.

[0099] In this application, through the coupling reaction of a chloroarene with a specific structure and (trialkylsilyl)acetylene under the synergistic catalysis of a Pd precatalyst and a phosphine ligand, and then through subsequent desilylation, aryl terminal alkynes are finally prepared. The chloroarene used as a raw material in the present invention is inexpensive and easily available, and the dosage of the Pd precatalyst is only 0.0008 molar equivalent of the chloroarene, thus significantly reducing the production cost; the Pd precatalyst with a specific structure and the phosphine ligand with a specific structure in this application can efficiently exert their synergistic catalytic effect, effectively improving the catalytic efficiency and the yield of the product. Finally, the yield of the prepared aryl terminal alkyne can be as high as 90%.

[0100] The following further elaborates on this application through specific examples. The following examples only further illustrate this application and should not be construed as a limitation of this application. In these examples, unless otherwise specified, the reagents and instruments used are commercially available, and the experimental operations are carried out in accordance with the product instructions and conventional experimental specifications.

[0101] Example

[0102] I. Investigation of the preparation of terminal alkynes:

[0103]

[0104] (1) Investigation of the combination of Pd precatalyst and ligand

[0105] Under a nitrogen atmosphere, 0.2 mmol of the compound shown in Formula I-1, 0.3 mmol of (triisopropylsilyl)acetylene, a Pd precatalyst (1.6×10 -4 mmol, see Table 1), a ligand (0.01 mmol, see Table 1), and the base Cs2CO3 (0.03 mmol) were mixed with 2.0 mL of a solvent, and then transferred to a reaction tube. Under a nitrogen reaction atmosphere, the reaction was carried out at 130 °C for 10 hours. Subsequently, the temperature was lowered to room temperature, 4.0 mL of ethyl acetate was added for dilution, and the mixture was quenched with 8.0 mL of water. The organic phase was separated, the aqueous phase was washed twice with 2.0 mL of ethyl acetate, and then the organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was concentrated under reduced pressure to dryness to obtain a crude product, which was subsequently separated and purified by column chromatography to obtain the alkyne shown in Formula II-1a. The results are shown in Table 1.

[0106] Table 1: Investigation of Pd precatalyst and ligand combinations

[0107]

[0108] From the results in Table 1, it can be seen that compared with other Pd precatalysts, the use of Pd precatalysts XPhos-Pd-G1, XPhos-Pd-G2, XPhos-Pd-G3, and Pd(OAc)2 is more conducive to improving the yield of the obtained product. Compared with other ligands, the use of the ligand XPhos is more conducive to improving the yield of the obtained product. Among them, it is preferred to use the Pd precatalyst XPhos-Pd-G1 and the ligand XPhos, and the yield can be as high as 95%.

[0109] (2) Investigation of the base

[0110] Under a nitrogen atmosphere, 0.2 mmol of the compound shown in Formula I-1, 0.3 mmol of (triisopropylsilyl)acetylene, 0.01 mmol of the ligand XPhos, Pd precatalyst: XPhos-Pd-G1 (1.6×10 -4 mmol), and a base (0.03 mmol, see Table 2) were mixed with 2.0 mL of a solvent, and then transferred to a reaction tube. Under a nitrogen reaction atmosphere, the reaction was carried out at 130 °C for 10 h. Subsequently, the temperature was lowered to room temperature, 4.0 mL of ethyl acetate was added for dilution, and the mixture was quenched with 8.0 mL of water. The organic phase was separated, the aqueous phase was washed twice with 2.0 mL of ethyl acetate, and then the organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was concentrated under reduced pressure to dryness to obtain a crude product, which was subsequently separated and purified by column chromatography to obtain the alkyne shown in Formula II-1a. The results are shown in Table 2.

[0111] Table 2: Investigation of the base

[0112]

[0113] As can be seen from the results in Table 2, compared with other alkaline reagents, using cesium carbonate (Cs2CO3) is more conducive to improving the yield of the obtained product, and the yield can be as high as 95%.

[0114] (3) Investigation of solvents

[0115] Under a nitrogen atmosphere, 0.2 mmol of the compound shown in Formula I-1, 0.3 mmol of (triisopropylsilyl)acetylene, 0.01 mmol of the ligand XPhos, the Pd precatalyst: XPhos-Pd-G1 (1.6×10 -4 mmol), and the alkaline reagent Cs2CO3 (0.03 mmol) were mixed with the solvent (2.0 mL, see Table 3), then transferred to a reaction tube, and reacted at 130 °C for 10 hours under a nitrogen reaction atmosphere. Subsequently, it was cooled to room temperature, diluted with 4.0 mL of ethyl acetate, quenched with 8.0 mL of water, the organic phase was separated, the aqueous phase was washed twice with 2.0 mL of ethyl acetate, then the organic phases were combined, dried over anhydrous sodium sulfate, the solvent was concentrated under reduced pressure to dryness to obtain a crude product, and the subsequent purification by column chromatography gave the alkyne shown in Formula II-1a. The results are shown in Table 3.

[0116] Table 3: Investigation of solvents

[0117]

[0118] As can be seen from the results in Table 3, compared with other solvents, using o-xylene as the solvent is more conducive to improving the yield of the obtained product, and the yield can be as high as 95%.

[0119] (4) Investigation of fluorides (fluorinated salts) in the removal of TIPS

[0120] II-1a was dissolved in 1.0 mL of tetrahydrofuran, and 3.0 equivalents of the fluoride salt: TBAF (1 mol / L in THF) was added, and stirred at room temperature for 3 hours. The solvent was concentrated under reduced pressure, and the subsequent purification by column chromatography gave the terminal alkyne shown in Formula II-1.

[0121]

[0122] Table 4: Removal of TIPS

[0123]

[0124]

[0125] As can be seen from the results in Table 4, in the removal of TIPS, using THF as the solvent and TBAF as the base is conducive to improving the yield of the obtained product, and the yield can be as high as 90%.

[0126] II. Preparation of Terminal Alkynes of Chemical Formulas II-1 to II-12:

[0127] The reaction formula for preparing the terminal alkyne with the structure as described in Formula II is as follows:

[0128]

[0129] General synthesis method: Under a nitrogen atmosphere, 0.2 mmol of the compound shown in Formula I, 0.3 mmol of (triisopropylsilyl)acetylene, 0.01 mmol of XPhos ligand, 1.6×10 -4 mmol of Pd precatalyst XPhos-Pd-G1, and 0.03 mmol of basic reagent Cs2CO3 were mixed with 2.0 mL of solvent, and then transferred to a reaction tube. Under the reaction atmosphere of nitrogen, the reaction was carried out at a temperature of 130 °C for 10 hours. Subsequently, it was cooled to room temperature, diluted with 4.0 mL of ethyl acetate, quenched with 8.0 mL of water, the organic phase was separated, the aqueous phase was washed twice with 2.0 mL of ethyl acetate, then the organic phases were combined, dried over anhydrous sodium sulfate, the solvent was concentrated under reduced pressure to dryness to obtain the crude product. The crude product was dissolved in 1.0 mL of tetrahydrofuran, and 3.0 equivalents of fluoride salt: TBAF (1 mol / L in THF) was added, and stirred at room temperature for 3 hours. The solvent was concentrated under reduced pressure, and then separated and purified by column chromatography to obtain the terminal alkyne shown in Formula II.

[0130] Using the above general synthesis method, only replacing the compound of Formula I with one of the compounds of Formula I-1 to Formula I-12, the terminal alkynes shown in Formula II-1 to Formula II-12 were respectively prepared. Among them, the structures of the compounds of Formula I-1 to Formula I-12 are as follows:

[0131]

[0132] By 1 1H NMR and 13 13C NMR spectra to determine the structure of the hydrogenated product, and the structures of each product (compounds of Formula II-1 to Formula II-12) are as follows:

[0133]

[0134] Through separation for yield analysis, the yields of each product (compounds of Formula II-1 to Formula II-12) are as follows:

[0135]

[0136] In this example, the specific synthesis steps, product structures, and yield analysis data of some products are schematically listed as follows:

[0137] a) Synthesis of the terminal alkyne shown in II-1

[0138] Mix 0.2 mmol of the compound shown in Formula I-1, 0.3 mmol of (triisopropylsilyl)acetylene, 0.01 mmol of the ligand XPhos, 1.6×10 -4 mmol of the Pd precatalyst XPhos-Pd-G1 and 0.03 mmol of the base Cs2CO3 with 2.0 mL of the solvent, then transfer to a reaction tube, and react at 130 °C for 10 hours under a reaction atmosphere of nitrogen. Subsequently, cool to room temperature, dilute with 4.0 mL of ethyl acetate, quench with 8.0 mL of water, separate the organic phase, wash the aqueous phase twice with 2.0 mL of ethyl acetate, then combine the organic phases, dry with anhydrous sodium sulfate, concentrate the solvent under reduced pressure to obtain the crude product. Dissolve the crude product in 1.0 mL of tetrahydrofuran, add 3.0 equivalents of fluoride salt: TBAF (1.0 mol / L in THF), and stir at room temperature for 3 hours. Concentrate the solvent to dryness under reduced pressure, and then purify by column chromatography to obtain the terminal alkyne shown in Formula II-1 as a colorless oil, 22.4 mg; the NMR data of Product II-1 are 1 1H NMR (400 MHz, CDCl3) δ 8.09 (s, 1H), 7.94 (d, J = 7.9 Hz, 1H), 7.59 (d, J = 7.7 Hz, 1H), 7.33 (t, J = 7.8 Hz, 1H), 3.85 (s, 3H), 3.05 (s, 1H). 13 13C NMR (101 MHz, CDCl3) δ 166.3, 136.3, 133.4, 130.6, 129.9, 128.6, 122.7, 82.6, 78.2, 52.4.

[0139] Among them, the preparation of the Pd precatalyst XPhos-Pd-G1 (800 mol ppm catalyst for 0.2 mmol reaction): Dissolve XPhos-Pd-G1 (7.4 mg, 0.01 mmol, 0.05 equiv) in 5.0 mL of o-xylene, and then take 80 μL of the solution.

[0140] Colorless oil, 22.4 mg, 70% yield; the NMR data of Product II-1 are 1 1H NMR (400 MHz, CDCl3) δ 8.09 (s, 1H), 7.94 (d, J = 7.9 Hz, 1H), 7.59 (d, J = 7.7 Hz, 1H), 7.33 (t, J = 7.8 Hz, 1H), 3.85 (s, 3H), 3.05 (s, 1H). 13 13C NMR (101 MHz, CDCl3) δ 166.3, 136.3, 133.4, 130.6, 129.9, 128.6, 122.7, 82.6, 78.2, 52.4.

[0141] Among them, the 1H NMR spectrum and 13C NMR spectrum of the terminal alkyne shown in II-1 are shown in Figure 1 and Figure 2 respectively.

[0142] b) Synthesis of the terminal alkyne shown in II-2

[0143] Mix 0.2 mmol of the compound shown in Formula I-2, 0.3 mmol of (triisopropylsilyl)acetylene, 0.01 mmol of ligand XPhos, Pd precatalyst XPhos-Pd-G1 (1.6×10 -4 mmol), and 0.03 mmol of basic reagent Cs2CO3 with 2.0 mL of solvent, then transfer it to a reaction tube. Under the reaction atmosphere of nitrogen, react at a temperature of 130 °C for 10 h. Subsequently, cool to room temperature, dilute with 4.0 mL of ethyl acetate, quench with 8.0 mL of water, separate the organic phase, wash the aqueous phase twice with 2.0 mL of ethyl acetate, then combine the organic phases, dry with anhydrous sodium sulfate, concentrate the solvent under reduced pressure to obtain a crude product. Dissolve the crude product in 1.0 mL of tetrahydrofuran, add 3.0 equivalents of fluoride salt: TBAF (1 mol / L in THF), and stir at room temperature for 3 hours. Concentrate the solvent under reduced pressure, and then separate and purify by column chromatography to obtain the terminal alkyne shown in Formula II-2 as a colorless oil, 17.5 mg; the NMR data of product II-2 are 1 H NMR (400 MHz, CDCl3) δ 7.33 (d, J = 8.2 Hz, 2H), 7.18 (d, J = 8.2 Hz, 2H), 4.74 (q, J = 6.5 Hz, 1H), 2.92 (s, 1H), 1.33 (d, J = 6.5 Hz, 3H), 0.90 (s, 21H). 13 C NMR (101 MHz, CDCl3) δ 146.7, 132.4, 125.4, 121.2, 83.6, 70.1, 25.2, 17.8, 12.4.

[0144] The 1H NMR spectrum and 13C NMR spectrum of the terminal alkyne shown in II-2 are shown in Figure 3 and Figure 4 respectively.

[0145] c) Synthesis of the terminal alkyne shown in II-3

[0146] Mix 0.2 mmol of the compound shown in Formula I-3, 0.3 mmol of (triisopropylsilyl)acetylene, 0.01 mmol of ligand XPhos, Pd precatalyst XPhos-Pd-G1 (1.6×10 -4(0.2 mmol) and the base Cs2CO3 (0.03 mmol) were mixed with 2.0 mL of solvent, then transferred to a reaction tube. Under a nitrogen reaction atmosphere, the reaction was carried out at 130 °C for 10 h. Subsequently, it was cooled to room temperature, diluted with 4.0 mL of ethyl acetate, quenched with 8.0 mL of water, the organic phase was separated, the aqueous phase was washed twice with 2.0 mL of ethyl acetate, then the organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was concentrated under reduced pressure to obtain the crude product. The crude product was dissolved in 1.0 mL of tetrahydrofuran, and 3.0 equivalents of fluoride salt: TBAF (1 mol / L in THF) was added, and stirred at room temperature for 3 h. The solvent was concentrated under reduced pressure, and then separated and purified by column chromatography to obtain the terminal alkyne shown in formula II-3 as a colorless oil, 9.4 mg; the NMR data of product II-3 was 1 H NMR (600 MHz, CDCl3) δ 7.27 (d, J = 8.2 Hz, 2H), 6.55 (d, J = 8.2 Hz, 2H), 3.79 (s, 2H), 2.94 (s, 1H). 13 C NMR (151 MHz, CDCl3) δ 147.0, 133.4, 114.5, 111.2, 84.4, 74.9.

[0147] The 1H NMR spectrum and 13C NMR spectrum of the terminal alkyne shown in II-3 are shown in Figure 5 and Figure 6 .

[0148] d) Synthesis of the terminal alkyne shown in II-4

[0149] 0.2 mmol of the compound shown in formula I-4, 0.3 mmol of (triisopropylsilyl)acetylene, 0.01 mmol of ligand XPhos, Pd precatalyst XPhos-Pd-G1 (1.6×10 -4 mmol) and the base Cs2CO3 (0.03 mmol) were mixed with 2.0 mL of solvent, then transferred to a reaction tube. Under a nitrogen reaction atmosphere, the reaction was carried out at 130 °C for 10 h. Subsequently, it was cooled to room temperature, diluted with 4.0 mL of ethyl acetate, quenched with 8.0 mL of water, the organic phase was separated, the aqueous phase was washed twice with 2.0 mL of ethyl acetate, then the organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was concentrated under reduced pressure to obtain the crude product. The crude product was dissolved in 1.0 mL of tetrahydrofuran, and 3.0 equivalents of fluoride salt: TBAF (1 mol / L in THF) was added, and stirred at room temperature for 3 h. The solvent was concentrated under reduced pressure, and then separated and purified by column chromatography to obtain the terminal alkyne shown in formula II-4 as a colorless oil, 13.5 mg; the NMR data of product II-4 was 11H NMR (400 MHz, CDCl3) δ 7.92 (d, J = 8.3 Hz, 2H), 7.58 (d, J = 8.3 Hz, 2H), 3.27 (s, 1H), 2.61 (s, 3H). 13 13C NMR (101 MHz, CDCl3) δ 197.3, 136.8, 132.3, 128.2, 127.0, 82.8, 80.5, 26.7.

[0150] The 1H NMR spectrum and 13C NMR spectrum of the terminal alkyne shown in II-4 are shown in Figure 7 and Figure 8 respectively.

[0151] e) Synthesis of the terminal alkyne shown in II-5

[0152] 0.2 mmol of the compound shown in Formula I-4, 0.3 mmol of (triisopropylsilyl)acetylene, 0.01 mmol of ligand XPhos, Pd precatalyst XPhos-Pd-G1 (1.6×10 -4 mmol), and basic reagent Cs2CO3 (0.03 mmol) were mixed with 2.0 mL of solvent, then transferred to a reaction tube. Under a nitrogen reaction atmosphere, the reaction was carried out at 130 °C for 10 hours. Subsequently, the temperature was lowered to room temperature, 4.0 mL of ethyl acetate was added for dilution, quenched with 8.0 mL of water, the organic phase was separated, the aqueous phase was washed twice with 2.0 mL of ethyl acetate, then the organic phases were combined, dried over anhydrous sodium sulfate, the solvent was concentrated under reduced pressure to obtain a crude product. The crude product was dissolved in 1.0 mL of tetrahydrofuran, 3.0 equivalents of fluoride salt: TBAF (1 mol / L in THF) was added, and stirred at room temperature for 3 hours. The solvent was concentrated under reduced pressure, and then separated and purified by column chromatography to obtain the terminal alkyne shown in Formula II-1, which was a colorless oil, 25.2 mg; the NMR data of product II-5 were 1 1H NMR (400 MHz, CDCl3) δ 7.90 (s, 1H), 7.69–7.56 (m, 3H), 7.46–7.32 (m, 3H), 3.03 (s, 1H). 13 13C NMR (101 MHz, CDCl3) δ 133.1, 132.9, 132.4, 128.6, 128.1, 127.8, 127.0, 126.7, 119.5, 84.1, 77.6.

[0153] The 1H NMR spectrum and 13C NMR spectrum of the terminal alkyne shown in II-5 are shown in Figure 9 and Figure 10 respectively.

[0154] f) Synthesis of the terminal alkyne shown in II-6

[0155] 0.2 mmol of the compound shown in Formula I-4, 0.3 mmol of (triisopropylsilyl)acetylene, 0.01 mmol of ligand XPhos, Pd precatalyst XPhos-Pd-G1 (1.6×10 -4 mmol), and basic reagent Cs2CO3 (0.03 mmol) were mixed with 2.0 mL of solvent, then transferred to a reaction tube, and reacted at 130 °C for 10 h under a nitrogen reaction atmosphere. Subsequently, the temperature was lowered to room temperature, 4.0 mL of ethyl acetate was added for dilution, quenched with 8.0 mL of water, the organic phase was separated, the aqueous phase was washed twice with 2.0 mL of ethyl acetate, then the organic phases were combined, dried over anhydrous sodium sulfate, the solvent was concentrated under reduced pressure to obtain a crude product. Then the crude product was dissolved in 1.0 mL of tetrahydrofuran, 3.0 equivalents of fluoride salt: TBAF (1 mol / L in THF) was added, and stirred at room temperature for 3 hours. The solvent was concentrated under reduced pressure, and then separated and purified by column chromatography to obtain the terminal alkyne shown in Formula II-1, which was a colorless oil, 20.6 mg; the NMR data of product II-6 was 1 1H NMR (600 MHz, CDCl3) δ 7.61 (d, J = 8.0 Hz, 2H), 7.56 (d, J = 8.0 Hz, 2H), 3.30 (s, 1H). 13 13C NMR (151 MHz, CDCl3) δ 132.6, 132.0, 126.9, 118.2, 112.3, 81.8, 81.5.

[0156] The 1H NMR spectrum and 13C NMR spectrum of the terminal alkyne shown in II-6 are shown in Figure 11 and Figure 12 .

[0157] In summary, in this example, aryl chlorides shown in I-1 to I-12 were used to synthesize terminal alkynes shown in II-1 to II-12 respectively. The synthesis method of this example has the advantages of cheap and easily available raw materials, simple operation steps, high catalytic efficiency, high yield, etc.

[0158] The above content is a further detailed description of the present application in combination with specific embodiments, and it cannot be determined that the specific implementation of the present application is only limited to these descriptions. For those of ordinary skill in the technical field to which the present application belongs, without departing from the concept of the present application, several simple deductions or substitutions can also be made.

Claims

1. A method for preparing an aryl terminal alkyne, characterized in that, The preparation method includes the following steps: (1) (2) Among them, R1, R2, and R3 are each independently selected from: -H, C1-C 10 alkyl Ar is selected from one of the following structures: X is CH or N, R A Selected from: -H, -CN, -CO-(C6-C 10 aryl), R J and R K each independently selected from: -H, C1-C 10 alkyl, R B Selected from: -H, -(C0-C 10 alkylene)-NH2, -(C0-C 10 alkylene)-CO-(C1-C 10 alkyl), -(C0-C 10 alkylene)-CN, -(C0-C 10 alkylene)-(C6-C 10 aryl), -(C0-C 10 alkylene)-NO2, R C selected from: -H, -(C0-C 10 alkylene)-COO(C1-C 10 alkyl), R D Selected from: -H, C1-C 10 alkyl group Y is CH or N, Z is CH or N, R E 、R F 、R G 、R H 、R I Each independently selected from: -H, C1-C 10 alkyl; The precatalyst includes at least one of the following structures: The ligand includes at least one of the following structures:

2. The preparation method according to claim 1, characterized in that, The dosage of the precatalyst is 0.0001 - 0.001 molar equivalent of the compound shown in Structural Formula I; Preferably, the dosage of the precatalyst is 0.0008 molar equivalent of the compound shown in Structural Formula I; Preferably, the dosage of the ligand is 0.01 - 0.1 molar equivalent of the compound shown in Structural Formula I; Preferably, the dosage of the ligand is 0.05 molar equivalent of the compound shown in Structural Formula I.

3. The preparation method according to claim 1, characterized in that, R A Selected from -H, -CN, -CO-(C 6-8 aryl), R K Selected from: H, C 1-6 alkyl; Preferably, R A is selected from -H, -CN, -CO-phenyl; Preferably, R B is selected from -H, -NH2, -CO-(C1-C 10 alkyl), -CN, -(C6-C8 aryl), -NO2; Preferably, R B is selected from -H, -NH2, -CO-CH3, -CN, -phenyl, -NO2; Preferably, R C is selected from -H, -COO(C1-C 10 alkyl); Preferably, R C is selected from -H, -COOCH3; Preferably, R D is -H; Preferably, R E , R F , R G , R H , R I are each independently -H.

4. The preparation method according to claim 1 or 3, characterized in that, R1, R2, and R3 are each independently C 1-10 alkyl; Preferably, R1, R2, and R3 are each independently a C3 alkyl group; Preferably, R1, R2, and R3 are each independently an isopropyl group.

5. The preparation method according to claim 1, characterized in that, The structure of the compound of Formula I is at least one of I-1 to I-12: Preferably, the structure of the compound of Formula II is at least one of II-1 to II-12:

6. The preparation method according to claim 1, wherein, The basic reagent is selected from at least one of potassium carbonate, cesium carbonate, and potassium phosphate; Preferably, the addition amount of the basic reagent is 1.0 - 3.0 molar equivalents of the compound shown in Structural Formula I.

7. The preparation method according to claim 1, characterized in that, The first solvent is a benzene solvent or an ether solvent; Preferably, the first solvent is a benzene solvent; Preferably, the first solvent is selected from at least one of toluene, o-xylene, and mesitylene.

8. The preparation method according to claim 1, wherein The second solvent is selected from one of tetrahydrofuran, ethyl acetate, dichloromethane, and methanol; Preferably, the fluoride salt is selected from one of tetrabutylammonium fluoride, potassium fluoride, and cesium fluoride; Preferably, the addition amount of the fluoride salt is 1.0 - 10.0 molar equivalents of the compound shown in Structural Formula I; Preferably, the fluoride salt is tetrabutylammonium fluoride, and the addition amount is 3.0 molar equivalents of the compound shown in Structural Formula I.

9. The preparation method according to claim 1, wherein, The reaction temperature in step (1) is 20°C - 200°C; Preferably, the reaction time in step (1) is 5h - 15h; Preferably, the reaction temperature in step (2) is 20°C - 30°C; Preferably, the reaction time in step (2) is 1h - 10h.

10. The preparation method according to claim 1 or 9, characterized in that, Both step (1) and step (2) are carried out in an oxygen-free environment; Preferably, the oxygen-free environment is an inert gas atmosphere; Preferably, the inert gas is at least one of nitrogen, helium, neon, argon, krypton, and xenon; Preferably, the inert gas is nitrogen.

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