A 1,3-enyne compound synthesized by copper catalysis and its synthesis method

Abstract

The present invention discloses a copper-catalyzed synthesis method of 1,3-enyne compounds and the 1,3-enyne compounds synthesized thereby, belonging to the technical field of 1,3-enyne compound synthesis. Using 1,4-enyne compounds as substrates, MesCu as a catalyst, Xantphos or (R,R)-Ph-BPE as ligands, MeOH or t-BuOH as additives, and THF as a solvent, the reaction is carried out at -25 to 25 °C for 1 to 5 hours, followed by separation and purification to obtain trans-1,3-enynes or cis-1,3-enynes. By controlling the types of ligands and additives for synthesizing 1,3-enyne compounds, the cis-trans 1,3-enynes can be selectively regulated. The reaction conditions are mild, the reaction time is short, and the yield is high.

Description

Technical Field

[0001] The present invention relates to the technical field of the synthesis of 1,3-enyne compounds, and particularly to a 1,3-enyne compound synthesized by copper catalysis and a synthesis method thereof. Background Art

[0002] Compounds containing a conjugated 1,3-enyne structure are widely used in the fields of chemistry, biology, medicine, materials, etc. Terbinafine, Bupleurynol, Xerulin, and Oxamflatin, as representative bioactive molecules containing a 1,3-enyne structure, have important medicinal values. In addition, due to the diverse transformation potential of this structure, various functional structures can be synthesized through strategies such as regioselective reduction and stereodivergent tandem reactions, including conjugated olefins (Org. Lett. 2022, 24(29), 5486 - 5490), chiral propargylamines (Angew. Chem. Int. Ed. 2020, 59, 4879–4882), vinylsilanes (Acta Phys.-Chim. Sin. 2018, 34(6), 598–617), isoxazole derivatives (Chem. Commun., 2020, 56, 6253 - 6256), etc., providing new means for the development of novel organic materials and bioactive molecules with innovative structures. As shown below:

[0003]

[0004] In the current synthesis methods of cis- and trans-1,3-enynes, there are mainly the following several:

[0005] 1. Sonogashira coupling reaction (Tetrahedron 2006, 62, 112–120; Bull. Korean Chem. Soc. 2021, 42, 514–516), which is usually a cross-coupling reaction of vinyl halides and terminal alkynes catalyzed by copper / palladium. By using cis- or trans-vinyl halides, the corresponding single-configuration cis- or trans-1,3-enyne products can be obtained. This method has the following limitations: 1) The operation is complex and the reaction conditions are harsh, requiring reaction at high temperature; 2) Expensive and complex palladium is used as a catalyst, with high cost and the generation of palladium-containing waste; 3) The reagents are highly toxic and the functional group compatibility is poor; 4) It can only regulate the formation of one configuration of enyne according to the cis-trans structure of the starting olefin, limiting the wide industrial application of this method.

[0006] 2. Propargyl alcohol dehydrates to form cis-1,3-enynes under iron catalysis (Org. Lett. 2012, 14, 9, 2358–2361). This method also has limitations: 1) It can only form a single cis-enyne with cis-olefins; 2) The reaction conditions are harsh, requiring a high temperature of 60 °C; 3) The catalyst loading is large and the efficiency is not high.

[0007] 3. Terminal alkynes can regulate cis- and trans-products by controlling ligands or bases under metal catalysis (Synlett, 1999, 281–287; ACS Omega 2018, 3, 5071-5077). Although this method can achieve the simultaneous regulation of two configurations, it has the following limitations: 1) The operation is complex, the reaction conditions are harsh, and the reaction needs to be carried out under high temperature conditions; 2) It is limited to aromatic compounds; 3) The selectivity is poor; 4) Side reactions are likely to occur: the dimerization reaction of terminal alkynes.

[0008] Therefore, the development of an efficient synthetic method capable of regulating the cis-trans selectivity of 1,3-enynes is of great significance and will greatly promote the wide application of 1,3-enyne compounds in the industrial field. Summary of the Invention

[0009] To solve the above problems, the present invention provides a copper-catalyzed synthetic method for selectively regulating cis-trans 1,3-enynes, and specifically provides a 1,3-enyne compound synthesized by copper catalysis and its synthetic method.

[0010] To achieve the above object, the present invention provides the following scheme:

[0011] The present invention provides a method for synthesizing 1,3-enyne compounds by copper catalysis. Under a protective atmosphere, a 1,4-enyne compound represented by formula I is used as a substrate, MesCu is used as a catalyst, Xantphos or (R,R)-Ph-BPE is used as a ligand, methanol (MeOH) or t-BuOH is used as an additive, and tetrahydrofuran (THF) is used as a solvent. The reaction is carried out at -25 to 25 °C for 1 to 5 hours, and after separation and purification, a trans-1,3-enyne represented by formula II or a cis-1,3-enyne represented by formula III is obtained;

[0012]

[0013] In the general structural formula of the 1,4-enyne compound and the general structural formulas of the cis- and trans-1,3-enynes, R1 is a substituted or unsubstituted aromatic ring, heteroaromatic ring, and alkyl substituent; substitution includes mono- to trisubstitution, and the substituents are selected from tert-butyl, methoxy, halogen, halogen-substituted alkyl, cyano, aryl, substituted aryl, silyl, silylbenzene, and trifluoromethyl; R2, R3, and R4 are all H or alkyl, halogen, halogen-substituted alkyl, cyano, aryl, substituted aryl, silyl, silylbenzene, and trifluoromethyl.

[0014] Further, when preparing the trans-1,3-enyne shown in Formula II: Under a protective atmosphere, using the 1,4-enyne compound shown in Formula I as a substrate, MesCu as a catalyst, Xantphos as an achiral ligand for constructing the trans-1,3-enyne, MeOH as an additive, and THF as a solvent, reacting at -25 to 25 °C for 1 to 5 hours, followed by separation and purification;

[0015] When preparing the cis-1,3-enyne shown in Formula III: Under a protective atmosphere, using the 1,4-enyne compound shown in Formula I as a substrate, MesCu as a catalyst, (R,R)-Ph-BPE as a chiral bisphosphine heterocyclic ligand for constructing the cis-1,3-enyne, t-BuOH as an additive, and THF as a solvent, reacting at -25 to 25 °C for 1 to 5 hours, followed by separation and purification;

[0016]

[0017] Among them, R1 is a substituted or unsubstituted aromatic ring, heteroaromatic ring, and alkyl substituent; substitution includes mono- to trisubstitution, and the substituents are selected from tert-butyl, methoxy, halogen, halogen-substituted alkyl, cyano, aryl, substituted aryl, silyl, silylbenzene, and trifluoromethyl; R2, R3, and R4 are all H or alkyl, halogen, halogen-substituted alkyl, cyano, aryl, substituted aryl, silyl, silylbenzene, and trifluoromethyl.

[0018] Further, when preparing the cis-1,3-enyne shown in Formula III, it specifically includes the following steps:

[0019] 1) Under nitrogen protection, add the catalyst MesCu, the chiral bisphosphine heterocyclic ligand (R,R)-Ph-BPE, the additive t-BuOH, and the solvent THF to the reaction vessel, and complex and stir at room temperature for 10 minutes;

[0020] 2) Add the substrate 1,4-enyne compound shown in Formula I and react at -25 to 25 °C for 1 to 5 h;

[0021] 3) After the reaction is completed, perform column chromatography separation, the eluent is n-hexane, collect the eluate of the target compound, remove the solvent and dry it to finally obtain the cis-1,3-enyne shown in Formula III;

[0022]

[0023] Among them, R1 is a substituted or unsubstituted aromatic ring, heteroaromatic ring, and alkyl substituent; the substitution includes mono- to trisubstitution, and the substituents are selected from tert-butyl, methoxy, halogen, halogen-substituted alkyl, cyano, aryl, substituted aryl, silyl, silylbenzene, trifluoromethyl; R2, R3, and R4 are all H or alkyl, halogen, halogen-substituted alkyl, cyano, aryl, substituted aryl, silyl, silylbenzene, trifluoromethyl.

[0024] Further, when preparing the cis-1,3-enyne shown in Formula III, the dosage of the catalyst MesCu is 1-20% of the molar dosage of the 1,4-enyne compound, preferably 5%;

[0025] The dosage of the chiral bisphosphine heterocyclic ligand (R,R)-Ph-BPE is 1-20% of the molar dosage of the 1,4-enyne compound, preferably 5%;

[0026] The dosage of the additive t-BuOH is 0.5-2 times the molar dosage of the 1,4-enyne compound, preferably 1 time.

[0027] Further, the dosage of the solvent tetrahydrofuran is 0.1-1 M, preferably 0.2 M; the reaction temperature is preferably 20 °C; the reaction time is preferably 3 h.

[0028] Further, when preparing the trans-1,3-enyne shown in Formula II, it specifically includes the following steps:

[0029] 1) Under nitrogen protection, add the catalyst MesCu, the achiral ligand Xantphos, the additive MeOH, and the solvent THF to the reaction vessel, and complex and stir at room temperature for 10 minutes;

[0030] 2) Add the substrate 1,4-enyne compound shown in Formula I, and react at -25 to 25 °C for 1-5 h;

[0031] 3) After the reaction is completed, perform column chromatography separation, the eluent is n-hexane, collect the eluate of the target compound, remove the solvent and dry it, and finally obtain the trans-1,3-enyne shown in Formula II;

[0032]

[0033] Among them, R1 is a substituted or unsubstituted aromatic ring, heteroaromatic ring, and alkyl substituent; the substitution includes mono- to trisubstitution, and the substituents are selected from tert-butyl, methoxy, halogen, halogen-substituted alkyl, cyano, aryl, substituted aryl, silyl, silylbenzene, trifluoromethyl; R2, R3, and R4 are all H or alkyl, halogen, halogen-substituted alkyl, cyano, aryl, substituted aryl, silyl, silylbenzene, trifluoromethyl.

[0034] Furthermore, when preparing the trans-1,3-enyne shown in Formula II, the amount of the catalyst MesCu used is 1-20% of the molar amount of the 1,4-enyne compound, preferably 10%;

[0035] The amount of the achiral ligand Xantphos used is 1-20% of the molar amount of the 1,4-enyne compound, preferably 10%;

[0036] The amount of the additive MeOH used is 0.5-2 times the molar amount of the 1,4-enyne compound, preferably 0.5 times.

[0037] Furthermore, the amount of the solvent tetrahydrofuran used is 0.1-1 M, preferably 0.2 M; the reaction temperature is preferably 20 °C; the reaction time is preferably 3 h.

[0038] Furthermore, the structural formula of the 1,4-enyne compound is as follows:

[0039]

[0040] A 1,3-enyne compound synthesized by copper catalysis is synthesized by the method for synthesizing a 1,3-enyne compound by copper catalysis.

[0041] The present invention discloses a method for synthesizing a copper-catalyzed selective regulation of cis- and trans-1,3-enynes. Compared with the traditional Sonogashira coupling method, the present invention has the following advantages:

[0042] (1) The reaction conditions of the present invention are mild, the time is short, the yield is high, and the use of expensive palladium catalysts is avoided;

[0043] (2) The method provided by the present invention can generate high chemical reactivity and stereoselectivity through the regulation of ligands, and can efficiently and selectively obtain cis-enynes and trans-enynes;

[0044] (3) The catalytic system of the present invention has strong substrate universality, and enynes containing various functional groups can be efficiently converted;

[0045] (4) The operation of the present invention is simple, and the reaction device is simple. Compared with the traditional method, the present invention only needs to use a simple reaction flask, and the method is simple and convenient, suitable for large-scale production, and has good application prospects. Detailed Embodiments

[0046] The various exemplary embodiments of the present invention will now be described in detail. This detailed description should not be considered as a limitation of the present invention, but should be understood as a more detailed description of certain aspects, characteristics, and implementation schemes of the present invention.

[0047] It should be understood that the terms described in the present invention are only for describing specific embodiments and are not intended to limit the present invention. Additionally, for the numerical ranges in the present invention, it should be understood that each intermediate value between the upper and lower limits of the range is also specifically disclosed. Any intermediate value within any stated value or stated range, as well as each smaller range between any other stated value or intermediate value within the stated range, is also included in the present invention. The upper and lower limits of these smaller ranges may be independently included or excluded from the range.

[0048] Unless otherwise specified, all technical and scientific terms used herein have the same meaning as commonly understood by those of ordinary skill in the art to which the present invention pertains. Although the present invention only describes preferred methods and materials, any methods and materials similar or equivalent to those described herein may also be used in the practice or testing of the present invention. All documents mentioned in this specification are incorporated by reference to disclose and describe the methods and / or materials related to the documents. In case of conflict with any incorporated document, the content of this specification shall prevail.

[0049] Without departing from the scope or spirit of the present invention, various improvements and variations can be made to the specific embodiments of the present invention specification, which are obvious to those skilled in the art. Other embodiments obtained from the specification of the present invention are obvious to those skilled in the art. The specification and examples of the present invention are merely exemplary.

[0050] Regarding the use of "comprising", "including", "having", "containing", etc. herein, they are all open-ended terms, meaning including but not limited to.

[0051] The room temperature in the embodiments of the present invention refers to 25 ± 2 °C.

[0052] (1) The present invention provides a method for efficiently synthesizing trans - 1,3 - enynes, and the reaction equation is as follows:

[0053]

[0054] The synthesis steps are as follows:

[0055] ① Under nitrogen protection, add the catalyst MesCu (0.01 - 0.04 mmol, 5 - 20 mol%), the ligand Xantphos (0.01 - 0.04 mmol, 5 - 20 mol%), the additive MeOH (0.1 - 0.4 mmol, 0.5 - 2 equiv.) and the organic solvent THF (0.2 - 1 mL) to a reaction flask with a magnetic stir bar, and stir for complexation at room temperature for 10 minutes;

[0056] ② Add the substrate 1,4 - enyne compound shown in formula I and react at - 25 to 25 °C for 1 - 5 h;

[0057] ③ After the reaction is completed, the reaction mixture is separated by column chromatography using n-hexane as the eluent, and the solvent is removed by rotary evaporation to obtain the product trans-1,3-enyne shown in Formula II;

[0058]

[0059] In the general structural formula of 1,4-enyne compounds and the general structural formula of trans-1,3-enyne, R1 is a substituted or unsubstituted aromatic ring, heteroaromatic ring, and alkyl substituent; substitution includes mono- to trisubstitution, and the substituents are selected from tert-butyl, methoxy, halogen, halogen-substituted alkyl, cyano, aryl, substituted aryl, silyl, silylbenzene, and trifluoromethyl; R2, R3, and R4 are all H or alkyl, halogen, halogen-substituted alkyl, cyano, aryl, substituted aryl, silyl, silylbenzene, and trifluoromethyl.

[0060] The present invention will be further described below with specific examples.

[0061]

[0062] Example 1

[0063] Under a nitrogen atmosphere, MesCu (0.02 mmol, 10 mol%) and Xantphos (0.02 mmol, 10 mol%) and MeOH (0.1 mmol, 0.5 equiv.) were added to a reaction vessel with a magnetic stirrer, and then the organic solvent THF (1 mL) was added and stirred at room temperature for complexation for 10 minutes. Finally, 4-phenyl-1-penten-4-yne (0.2 mmol) was added, and the reaction was carried out at 0 - 5 °C for 1 hour. After the reaction was completed, the reaction mixture was separated by column chromatography using n-hexane as the eluent, and the solvent was removed by rotary evaporation and dried. Finally, 26.4 mg of pure product of compound II-1 was obtained with a yield of 93.3% and an E / Z ratio of 10.2:1.

[0064] 1 H NMR (400 MHz, DMSO-d6) δ (isom E) 7.40–7.36 (m, 2H), 7.35–7.31 (m, 3H), 6.21 (dd, J = 15.8, 6.8 Hz, 1H), 5.83–5.74 (m, 1H), 1.78 (dd, J = 6.8, 1.8 Hz, 3H).

[0065] 13 C NMR (101 MHz, DMSO-d6) δ (isom E) 141.10, 131.62, 129.20, 128.87, 110.99, 89.07, 88.18, 19.10.

[0066] Example 2

[0067] In a nitrogen atmosphere, MesCu (0.02 mmol, 10 mol%), Xantphos (0.02 mmol, 10 mol%), and MeOH (0.1 mmol, 0.5 equiv.) were added to a reaction vessel equipped with a magnetic stir bar. Then, the organic solvent THF (1 mL) was added, and the mixture was stirred at room temperature for 10 minutes for complexation. Finally, 4-methylphenyl-1-penten-4-yne (0.2 mmol) was added, and the reaction was carried out at 0 - 5 °C for 1 hour. After the reaction was completed, the reaction mixture was separated by column chromatography using n-hexane as the eluent. The solvent was removed by rotary evaporation and dried. Finally, 28.0 mg of pure compound II-2 was obtained with a yield of 90.1% and an E / Z ratio of 7.7:1.

[0068] 1 H NMR (400 MHz, DMSO-d6) δ (isom E) 7.27 (d, J = 8.1 Hz, 2H), 7.14 (d, J = 7.9 Hz, 2H), 6.17 (dd, J = 15.8, 6.8 Hz, 1H), 5.80–5.73 (m, 1H), 2.27 (s, 3H), 1.77 (dd, J = 6.8, 1.8 Hz, 3H).

[0069] 13 C NMR (101 MHz, DMSO-d6) δ (isom E) 140.54, 138.54, 131.52, 129.80, 120.29, 111.12, 88.41, 88.33, 21.50, 19.04.

[0070] Example 3

[0071] In a nitrogen atmosphere, MesCu (0.02 mmol, 10 mol%), Xantphos (0.02 mmol, 10 mol%), and MeOH (0.1 mmol, 0.5 equiv.) were added to a reaction vessel equipped with a magnetic stir bar. Then, the organic solvent THF (1 mL) was added, and the mixture was stirred at room temperature for 10 minutes for complexation. Finally, 2-methylphenyl-1-penten-4-yne (0.2 mmol) was added, and the reaction was carried out at 0 - 5 °C for 1 hour. After the reaction was completed, the reaction mixture was separated by column chromatography using n-hexane as the eluent. The solvent was removed by rotary evaporation and dried. Finally, 28.4 mg of pure compound II-3 was obtained with a yield of 91.1% and an E / Z ratio of 6.9:1.

[0072] 11H NMR (400 MHz, DMSO-d6) δ (isom E) 7.33 (d, J = 7.3 Hz, 1H), 7.26–7.21 (m, 2H), 7.16–7.11 (m, 1H), 6.21 (dd, J = 15.8, 6.8 Hz, 1H), 5.81 (dd, J = 15.8, 1.8 Hz, 1H), 2.32 (s, 3H), 1.78 (dd, J = 6.8, 1.8 Hz, 3H).

[0073] 13 13C NMR (101 MHz, DMSO-d6) δ (isom E) 140.78, 139.75, 131.86, 130.04, 128.81, 126.39, 123.10, 111.18, 92.96, 86.93, 20.78, 19.05.

[0074] Example 4

[0075] Under a nitrogen atmosphere, MesCu (0.02 mmol, 10 mol%), Xantphos (0.02 mmol, 10 mol%) and MeOH (0.1 mmol, 0.5 equiv.) were added to a reaction vessel equipped with a magnetic stir bar, and then the organic solvent THF (1 mL) was added. The mixture was stirred at room temperature for 10 minutes for complexation. Finally, 4-(m-tolyl)-1-penten-4-yne (0.2 mmol) was added, and the reaction was carried out at 0 - 5 °C for 1 hour. After the reaction was completed, the reaction mixture was separated by column chromatography using n-hexane as the eluent. The solvent was removed by rotary evaporation and dried. Finally, 28.7 mg of pure compound II-4 was obtained with a yield of 91.9% and an E / Z ratio of 8.7:1.

[0076] 1 1H NMR (400 MHz, DMSO-d6) δ (isom E) 7.22–7.19 (m, 2H), 7.16 (d, J = 13.4 Hz, 2H), 6.19 (dd, J = 15.8, 6.8 Hz, 1H), 5.77 (dt, J = 15.8, 1.7 Hz, 1H), 2.25 (s, 3H), 1.78 (dd, J = 6.8, 1.8 Hz, 3H).

[0077] 13 13C NMR (101 MHz, DMSO-d6) δ (isom E) 140.94, 138.49, 132.06, 129.63, 129.08, 128.71, 123.12, 111.04, 88.75, 88.32, 21.24, 19.09.

[0078] Example 5

[0079] In a nitrogen atmosphere, MesCu (0.02 mmol, 10 mol%), Xantphos (0.02 mmol, 10 mol%) and MeOH (0.1 mmol, 0.5 equiv.) were added to a reaction vessel equipped with a magnetic stir bar. Then, the organic solvent THF (1 mL) was added and stirred at room temperature for 10 minutes for complexation. Finally, 3-(pent-4-en-1-ynyl)thiophene (0.2 mmol) was added, and the reaction was carried out at 0 - 5 °C for 1 hour. After the reaction was completed, the reaction mixture was separated by column chromatography using n-hexane as the eluent, and the solvent was removed by rotary evaporation and dried. Finally, 27.3 mg of pure compound II-5 was obtained with a yield of 92.4% and an E / Z ratio of 8:1.

[0080] 1 H NMR (400 MHz, DMSO-d6) δ (isom E) 7.76–7.65 (m, 1H), 7.58–7.52 (m, 1H), 7.11 (dd, J = 5.0, 1.2 Hz, 1H), 6.17 (dd, J = 15.8, 6.8 Hz, 1H), 5.75 (dd, J = 15.8, 1.8 Hz, 1H), 1.76 (dd, J = 6.8, 1.8 Hz, 3H).

[0081] 13 C NMR (101 MHz, DMSO-d6) δ (isom E) 140.61, 130.03, 127.26, 111.00, 88.31, 83.69, 19.08.

[0082] Example 6

[0083] In a nitrogen atmosphere, MesCu (0.02 mmol, 10 mol%), Xantphos (0.02 mmol, 10 mol%) and MeOH (0.1 mmol, 0.5 equiv.) were added to a reaction vessel equipped with a magnetic stir bar. Then, the organic solvent THF (1 mL) was added and stirred at room temperature for 10 minutes for complexation. Finally, 1-fluoro-4-(pent-4-en-1-ynyl)benzene (0.2 mmol) was added, and the reaction was carried out at 0 - 5 °C for 1 hour. After the reaction was completed, the reaction mixture was separated by column chromatography using n-hexane as the eluent, and the solvent was removed by rotary evaporation and dried. Finally, 30.0 mg of pure compound II-6 was obtained with a yield of 93.6% and an E / Z ratio of 7.2:1.

[0084] 11H NMR (400 MHz, DMSO-d6) δ (isom E) δ 7.44 (dd, J = 8.9, 5.5 Hz, 2H), 7.19 (d, J = 9.0 Hz, 2H), 6.21 (dd, J = 15.8, 6.8 Hz, 1H), 5.76 (dd, J = 15.8, 1.7 Hz, 1H), 1.77 (dd, J = 6.8, 1.8 Hz, 3H).

[0085] 13 13C NMR (101 MHz, DMSO-d6) δ (isom E) 141.70, 133.54, 133.34, 129.35, 122.17, 110.78, 90.16, 87.01, 19.12.

[0086] 19 19F NMR (376 MHz, DMSO-d6) (isom E) δ -111.08.

[0087] Example 7

[0088] Under a nitrogen atmosphere, MesCu (0.02 mmol, 10 mol%), Xantphos (0.02 mmol, 10 mol%) and MeOH (0.1 mmol, 0.5 equiv.) were added to a reaction vessel equipped with a magnetic stir bar, and then the organic solvent THF (1 mL) was added. The mixture was stirred at room temperature for complexation for 10 minutes. Finally, 1-chloro-4-(pent-4-en-1-ynyl)benzene (0.2 mmol) was added, and the reaction was carried out at 0 - 5 °C for 1 hour. After the reaction was completed, the reaction mixture was separated by column chromatography using n-hexane as the eluent. The solvent was removed by rotary evaporation and dried. Finally, 30.3 mg of pure compound II-7 was obtained with a yield of 86% and an E / Z ratio of 5.3:1.

[0089] 1 1H NMR (400 MHz, DMSO-d6) δ (isom E) 7.39 (m, 4H), 6.23 (dd, J = 15.8, 6.8 Hz, 1H), 5.77 (dd, J = 15.9, 1.8 Hz, 1H), 1.78 (dd, J = 6.8, 1.8 Hz, 3H).

[0090] 13C NMR (101 MHz, DMSO-d6) δ (isom E) 141.19, 139.83, 133.93, 133.85, 116.54, 110.87, 88.76, 87.10, 19.07.

[0091] Example 8

[0092] In a nitrogen atmosphere, MesCu (0.02 mmol, 10 mol%), Xantphos (0.02 mmol, 10 mol%) and MeOH (0.1 mmol, 0.5 equiv.) were added to a reaction vessel equipped with a magnetic stir bar, and then the organic solvent THF (1 mL) was added. The mixture was stirred at room temperature for complexation for 10 minutes. Finally, 1-bromo-4-(pent-4-en-1-ynyl)benzene (

[0093] 0.2 mmol) was added, and the reaction was carried out at 0 - 5 °C for 1 hour. After the reaction was completed, the reaction mixture was separated by column chromatography using n-hexane as the eluent. The solvent was removed by rotary evaporation and dried. Finally, 38.6 mg of pure compound II-8 was obtained with a yield of 87.8% and an E / Z ratio of 6.1:1.

[0094] 1 H NMR (400 MHz, DMSO-d6) δ (isom E) 7.52 (d, J = 8.5 Hz, 2H), 7.32 (d, J = 8.5 Hz, 2H), 6.23 (dd, J = 15.8, 6.8 Hz, 1H), 5.80–5.74 (m, 1H), 1.77 (dd, J = 6.8, 1.8 Hz, 3H).

[0095] 13 C NMR (101 MHz, DMSO-d6) δ (isom E) 141.72, 133.53, 132.23, 122.53, 122.18, 110.80, 90.31, 87.10, 19.13.

[0096] Example 9

[0097] In a nitrogen atmosphere, MesCu (0.02 mmol, 10 mol%), Xantphos (0.02 mmol, 10 mol%) and MeOH (0.1 mmol, 0.5 equiv.) were added to a reaction vessel equipped with a magnetic stir bar, and then the organic solvent THF (1 mL) was added. The mixture was stirred at room temperature for complexation for 10 minutes. Finally, 1-(pent-4-en-1-ynyl)cyclohex-1-ene (0.2 mmol) was added, and the reaction was carried out at 0 - 5 °C for 1 hour. After the reaction was completed, the reaction mixture was separated by column chromatography using n-hexane as the eluent. The solvent was removed by rotary evaporation and dried. Finally, 27.3 mg of pure compound II-9 was obtained with a yield of 93.4% and an E / Z ratio of 6.3:1.

[0098] 11H NMR (400 MHz, DMSO-d6) δ (isom E) 6.07–5.99 (m, 1H), 5.98 (d, J = 3.9 Hz, 1H), 5.63 (dd, J = 15.7, 1.8 Hz, 1H), 2.05–1.99 (m, 4H), 1.72 (dd, J = 6.8, 1.8 Hz, 3H), 1.56–1.47 (m, 4H).

[0099] Example 10

[0100] Under a nitrogen atmosphere, MesCu (0.02 mmol, 10 mol%), Xantphos (0.02 mmol, 10 mol%) and MeOH (0.1 mmol, 0.5 equiv.) were added to a reaction vessel equipped with a magnetic stir bar, and then organic solvent THF (1 mL) was added. The mixture was stirred at room temperature for complexation for 10 minutes. Finally, 1-(pent-4-en-1-ynyl)-4-(trifluoromethyl)benzene (0.2 mmol) was added, and the reaction was carried out at 0 - 5 °C for 1 hour. After the reaction was completed, the reaction mixture was separated by column chromatography using n-hexane as the eluent. The solvent was removed by rotary evaporation and dried. Finally, 37.0 mg of pure compound II-10 was obtained with a yield of 88% and an E / Z ratio of 6.5:1.

[0101] 1 1H NMR (400 MHz, DMSO-d6) δ (isom E) 7.68 (d, J = 8.1 Hz, 2H), 7.60–7.57 (m, 2H), 6.30 (dd, J = 15.8, 6.8 Hz, 1H), 5.85–5.79 (m, 1H), 1.79 (dd, J = 6.8, 1.8 Hz, 3H).

[0102] 13 13C NMR (101 MHz, DMSO-d6) δ (isom E) 142.76, 132.32, 129.82, 127.58, 126.05, 126.01, 91.74, 86.78, 19.14.

[0103] 19 19F NMR (376 MHz, DMSO-d6) δ (isom E) -61.27.

[0104] Example 11

[0105] In a nitrogen atmosphere, MesCu (0.02 mmol, 10 mol%), Xantphos (0.02 mmol, 10 mol%) and MeOH (0.1 mmol, 0.5 equiv.) were added to a reaction vessel with a magnetic stir bar, and then the organic solvent THF (1 mL) was added. The mixture was stirred at room temperature for complexation for 10 minutes. Finally, 1-methyl-3-(pent-4-en-1-ynyl)-1H-pyrazole (0.2 mmol) was added, and the reaction was carried out at 0 - 5 °C for 1 hour. After the reaction was completed, the reaction mixture was separated by column chromatography using n-hexane as the eluent. The solvent was removed by rotary evaporation and dried. Finally, 26.4 mg of pure compound II-11 was obtained with a yield of 90.3% and an E / Z ratio of 6:1.

[0106] 1 H NMR (400 MHz, DMSO-d6) δ (isom E) 7.89 (s), 7.52 (d, J = 0.5 Hz), 6.08 (dd, J = 15.8, 6.8 Hz), 5.71 (dd, J = 15.8, 1.8 Hz), 3.77 (s, 3H), 1.74 (dd, J = 6.8, 1.8 Hz).

[0107] 13 C NMR (101 MHz, DMSO-d6) δ (isom E) 141.44, 139.27, 133.74, 111.31, 102.55, 88.99, 80.22, 39.18, 18.96.

[0108] Example 12

[0109] In a nitrogen atmosphere, MesCu (0.02 mmol, 10 mol%), Xantphos (0.02 mmol, 10 mol%) and MeOH (0.1 mmol, 0.5 equiv.) were added to a reaction vessel with a magnetic stir bar, and then the organic solvent THF (1 mL) was added. The mixture was stirred at room temperature for complexation for 10 minutes. Finally, 1-(pent-4-en-1-ynyl)-4-cyanobenzene (0.2 mmol) was added, and the reaction was carried out at 0 - 5 °C for 1 hour. After the reaction was completed, the reaction mixture was separated by column chromatography using n-hexane as the eluent. The solvent was removed by rotary evaporation and dried. Finally, 11.5 mg of pure compound II-12 was obtained with a yield of 34% and an E / Z ratio of 3.4:1.

[0110] 11H NMR (400 MHz, DMSO-d6) δ (isom E) 7.85–7.81 (m, 2H), 7.61–7.57 (m, 2H), 6.41–6.30 (m, 1H), 5.86 (m, 1H), 1.83 (dd, J = 6.8, 1.8 Hz, 3H).

[0111] Example 13

[0112] Under a nitrogen atmosphere, MesCu (0.02 mmol, 10 mol%), Xantphos (0.02 mmol, 10 mol%) and MeOH (0.1 mmol, 0.5 equiv.) were added to a reaction vessel equipped with a magnetic stir bar, and then the organic solvent THF (1 mL) was added. The mixture was stirred at room temperature for complexation for 10 minutes. Finally, 1-(pent-4-en-1-ynyl)-3-fluorobenzene (0.2 mmol) was added, and the reaction was carried out at -40 °C for 1 hour. After the reaction was completed, the reaction mixture was separated by column chromatography using n-hexane as the eluent. The solvent was removed by rotary evaporation and dried. Finally, 33.6 mg of the pure product of compound II-13 was obtained, with a yield of 89.7% and an E / Z ratio of 5.5:1.

[0113] 1 1H NMR (400 MHz, DMSO-d6) δ (isom E) 7.41–7.34 (m, 1H), 7.25–7.20 (m, 2H), 7.18 (s, 1H), 6.25 (dd, J = 15.8, 6.8 Hz, 1H), 5.78 (dd, J = 15.8, 1.8 Hz, 1H), 1.78 (dd, J = 6.8, 1.8 Hz, 3H).

[0114] Example 14

[0115] Under a nitrogen atmosphere, MesCu (0.02 mmol, 10 mol%), Xantphos (0.02 mmol, 10 mol%) and MeOH (0.1 mmol, 0.5 equiv.) were added to a reaction vessel equipped with a magnetic stir bar, and then the organic solvent THF (400 μL) was added. The mixture was stirred at room temperature for complexation for 10 minutes. Finally, 4-naphthalen-1-ylpent-4-en-4-yne (0.2 mmol) was added, and the reaction was carried out at 0 - 5 °C for 5 hours. After the reaction was completed, the reaction mixture was separated by column chromatography using n-hexane as the eluent. The solvent was removed by rotary evaporation and dried. Finally, 35 mg of the pure product of compound II-14 was obtained, with a yield of 91.2% and an E / Z ratio of 6.1:1.

[0116] 11H NMR (400 MHz, DMSO-d6) δ (isom E) 8.00 (d, J = 0.9 Hz, 1H), 7.89–7.84 (m, 3H), 7.52–7.45 (m, 3H), 6.32–6.21 (m, 1H), 5.86–5.80 (m, 1H), 1.80 (dd, J = 6.8, 1.8 Hz, 3H).

[0117] 13 13C NMR (101 MHz, DMSO-d6) δ (isom E) 141.59 (s), 133.09 (s), 132.69 (s), 131.13 (s), 128.77 (s), 128.15 (s), 127.38 (s), 120.59 (s), 110.81 (s), 89.59 (s), 19.05 (s).

[0118] Example 15

[0119] Under a nitrogen atmosphere, MesCu (0.04 mmol, 20 mol%), Xantphos (0.04 mmol, 20 mol%), and MeOH (0.1 mmol, 0.5 equiv.), magnesium isopropoxide (0.1 mmol, 0.5 equiv.) were added to a reaction vessel with a magnetic stir bar. Then, the organic solvent THF (1 mL) was added and stirred at room temperature for complexation for 10 minutes. Finally, tert-butyldimethyl(4-penten-1-yn-1-yl)silane (0.2 mmol) was added, and the reaction was carried out at 0 - 5 °C for 1 hour. After the reaction was completed, the reaction mixture was separated by column chromatography using n-hexane as the eluent, the solvent was removed by rotary evaporation and dried. Finally, 25.8 mg of the pure compound II-15 was obtained with a yield of 71.5% and an E / Z ratio of 7:1.

[0120] 1 1H NMR (400 MHz, CDCl3) δ (isom E) 6.18 (m, 1H), 5.53–5.46 (m, 1H), 1.75 (dd, J = 6.8, 1.8 Hz, 3H), 0.91 (s, 9H), 0.08 (s, 6H).

[0121] (2) The present invention provides a method for efficiently synthesizing cis-1,3-enynes, and the reaction equation is as follows:

[0122]

[0123] The synthesis steps are as follows:

[0124] ① Under nitrogen protection, add the catalyst MesCu (0.01 - 0.04 mmol, 5 - 20 mol%), ligand (R,R)-Ph-BPE (0.01 - 0.04 mmol, 5 - 20 mol%), additive t-BuOH (0.1 - 0.4 mmol, 0.5 - 2 equiv.) and organic solvent THF (0.2 - 1 mL) into a reaction flask equipped with a magnetic stir bar, and stir for complexation at room temperature for 10 minutes;

[0125] ② Add the substrate 1,4-enyne compound shown in Formula I, and react at -25 to 5 °C for 1 - 5 h;

[0126] ③ After the reaction is completed, separate the reaction mixture by column chromatography, use n-hexane as the eluent, remove the solvent by rotary evaporation, and obtain the product cis-1,3-enyne shown in Formula III;

[0127]

[0128] Wherein, R1 is a substituted or unsubstituted aromatic ring, heteroaromatic ring and alkyl substituent; substitution includes mono- to trisubstitution, and the substituents are selected from tert-butyl, methoxy, halogen, halogen-substituted alkyl, cyano, aryl, substituted aryl, silyl, silylbenzene, trifluoromethyl; R2, R3, and R4 are all H or alkyl, halogen, halogen-substituted alkyl, cyano, aryl, substituted aryl, silyl, silylbenzene, trifluoromethyl.

[0129] The present invention will be further described below in conjunction with specific embodiments.

[0130] Example 16

[0131] In a nitrogen atmosphere, add MesCu (0.01 mmol, 5 mol%), (R,R)-Ph-BPE (0.01 mmol, 5 mol%) and t-BuOH (0.2 mmol, 1 equiv.) into a reaction vessel equipped with a magnetic stir bar, then add the organic solvent THF (1 mL), stir for complexation at room temperature for 10 minutes, and finally add 4-phenyl-1-penten-4-yne (0.2 mmol), and react at room temperature for 1 hour. After the reaction is completed, separate the reaction mixture by column chromatography, use n-hexane as the eluent, remove the solvent by rotary evaporation and dry, and finally obtain 23.6 mg of pure product of Compound III-1, with a yield of 83% and Z / E greater than 20:1.

[0132] 11H NMR (400 MHz, DMSO-d6) δ (isom Z) 7.44–7.40 (m, 2H), 7.35 (dd, J = 5.0, 1.8 Hz, 2H), 6.09 (dd, J = 10.7, 6.9 Hz, 1H), 5.75 (dd, J = 10.7, 1.7 Hz, 1H), 1.87 (dd, J = 6.8, 1.7 Hz, 3H).

[0133] Example 17

[0134] Under a nitrogen atmosphere, MesCu (0.01 mmol, 5 mol%), (R,R)-Ph-BPE (0.01 mmol, 5 mol%) and t-BuOH (0.2 mmol, 1 equiv.) were added to a reaction vessel equipped with a magnetic stir bar. Then, organic solvent THF (1 mL) was added and the mixture was stirred at room temperature for 10 minutes for complexation. Finally, 4-methylphenyl-1-penten-4-yne (0.2 mmol) was added and the reaction was carried out at room temperature for 1 hour. After the reaction was completed, the reaction mixture was separated by column chromatography using n-hexane as the eluent. The solvent was removed by rotary evaporation and dried. Finally, 23.4 mg of pure compound Ⅲ-2 was obtained with a yield of 77% and Z / E greater than 20:1.

[0135] 1 1H NMR (400 MHz, CDCl3) δ (isom Z) 7.37–7.25 (m, 2H), 7.13–7.05 (m, 2H), 6.05–5.95 (m, 1H), 5.67 (dd, J = 10.7, 1.6 Hz, 1H), 2.32 (s, 3H), 1.96–1.91 (m, 3H).

[0136] Example 18

[0137] Under a nitrogen atmosphere, MesCu (0.01 mmol, 5 mol%), (R,R)-Ph-BPE (0.01 mmol, 5 mol%) and t-BuOH (0.2 mmol, 1 equiv.) were added to a reaction vessel equipped with a magnetic stir bar. Then, organic solvent THF (1 mL) was added and the mixture was stirred at room temperature for 10 minutes for complexation. Finally, 2-methylphenyl-1-penten-4-yne (0.2 mmol) was added and the reaction was carried out at room temperature for 1 hour. After the reaction was completed, the reaction mixture was separated by column chromatography using n-hexane as the eluent. The solvent was removed by rotary evaporation and dried. Finally, 27.8 mg of pure compound Ⅲ-3 was obtained with a yield of 89% and Z / E greater than 20:1.

[0138] 11H NMR (400 MHz, DMSO-d6) δ (isom Z) 7.39–7.35 (m, 1H), 7.24 (dd, J = 6.6, 1.4 Hz, 2H), 7.16 (m, J = 6.5, 4.1, 3.6 Hz, 1H), 6.09 (dd, J = 10.7, 6.8 Hz, 1H), 5.80 (dt, J = 9.1, 1.7 Hz, 1H), 2.36 (s, 3H), 1.89 (dd, J = 6.8, 1.7 Hz, 3H).

[0139] Example 19

[0140] Under a nitrogen atmosphere, MesCu (0.01 mmol, 5 mol%), (R,R)-Ph-BPE (0.01 mmol, 5 mol%) and t-BuOH (0.2 mmol, 1 equiv.) were added to a reaction vessel equipped with a magnetic stir bar. Then, the organic solvent THF (1 mL) was added and the mixture was stirred at room temperature for 10 minutes for complexation. Finally, 3-methylphenyl-1-penten-4-yne (0.2 mmol) was added and the reaction was carried out at room temperature for 1 hour. After the reaction was completed, the reaction mixture was separated by column chromatography using n-hexane as the eluent. The solvent was removed by rotary evaporation and dried to finally obtain 24.4 mg of pure compound III-4 with a yield of 78% and Z / E greater than 20:1.

[0141] 1 1H NMR (400 MHz, CDCl3) δ (isom Z) 7.25–7.15 (m, 3H), 7.15–6.96 (m, 1H), 6.05–5.95 (m, 1H), 5.68–5.63 (m, 1H), 2.29 (s, 3H), 1.94–1.91 (m, 3H).

[0142] Example 20

[0143] Under a nitrogen atmosphere, MesCu (0.01 mmol, 5 mol%), (R,R)-Ph-BPE (0.01 mmol, 5 mol%) and t-BuOH (0.2 mmol, 1 equiv.) were added to a reaction vessel equipped with a magnetic stir bar. Then, the organic solvent THF (1 mL) was added and the mixture was stirred at room temperature for 10 minutes for complexation. Finally, 3-(pent-4-en-1-ynyl)thiophene (0.2 mmol) was added and the reaction was carried out at room temperature for 1 hour. After the reaction was completed, the reaction mixture was separated by column chromatography using n-hexane as the eluent. The solvent was removed by rotary evaporation and dried to finally obtain 23.7 mg of pure compound III-5 with a yield of 80% and Z / E greater than 20:1.

[0144] 11H NMR (400 MHz, CDCl3) δ (isom Z) 7.40 (dd, J = 3.0, 1.1 Hz, 1H), 7.25–7.23 (m, 1H), 7.09 (dd, J = 5.0, 1.1 Hz, 1H), 6.06–5.96 (m, 1H), 5.65 (m, 1.7 Hz, 1H), 1.92 (dd, J = 6.9, 1.7 Hz, 3H).

[0145] Example 21

[0146] Under a nitrogen atmosphere, MesCu (0.01 mmol, 5 mol%), (R,R)-Ph-BPE (0.01 mmol, 5 mol%) and t-BuOH (0.2 mmol, 1 equiv.) were added to a reaction vessel equipped with a magnetic stir bar. Then, organic solvent THF (1 mL) was added and the mixture was stirred at room temperature for 10 minutes for complexation. Finally, 1-fluoro-4-(pent-4-en-1-ynyl)benzene (0.2 mmol) was added and the reaction was carried out at room temperature for 1 hour. After the reaction was completed, the reaction mixture was separated by column chromatography using n-hexane as the eluent. The solvent was removed by rotary evaporation and dried to finally obtain 22.4 mg of pure compound Ⅲ-6 with a yield of 70% and Z / E greater than 20:1.

[0147] 1 1H NMR (400 MHz, CDCl3) δ (isom Z) 7.41–7.35 (m, 2H), 7.24–7.17 (m, 1H), 6.97 (m, 1H), 6.01 (dq, J = 10.7, 6.8 Hz, 1H), 5.64 (dq, J = 10.7, 1.6 Hz, 1H), 1.91 (dd, J = 6.9, 1.7 Hz, 3H).

[0148] Example 22

[0149] Under a nitrogen atmosphere, MesCu (0.01 mmol, 5 mol%), (R,R)-Ph-BPE (0.01 mmol, 5 mol%) and t-BuOH (0.2 mmol, 1 equiv.) were added to a reaction vessel equipped with a magnetic stir bar. Then, organic solvent THF (1 mL) was added and the mixture was stirred at room temperature for 10 minutes for complexation. Finally, 1-chloro-4-(pent-4-en-1-ynyl)benzene (0.2 mmol) was added and the reaction was carried out at room temperature for 1 hour. After the reaction was completed, the reaction mixture was separated by column chromatography using n-hexane as the eluent. The solvent was removed by rotary evaporation and dried to finally obtain 25.7 mg of pure compound Ⅲ-7 with a yield of 73% and Z / E greater than 20:1.

[0150] 11H NMR (400 MHz, CDCl3) δ (isom Z) 7.23–7.20 (m, 2H), 7.15–7.13 (m, 2H), 5.96–5.86 (m, 1H), 5.57–5.50 (m, 1H), 1.81 (dd, J = 6.9, 1.7 Hz, 3H).

[0151] Example 23

[0152] Under a nitrogen atmosphere, MesCu (0.01 mmol, 5 mol%), (R,R)-Ph-BPE (0.01 mmol, 5 mol%) and t-BuOH (0.2 mmol, 1 equiv.) were added to a reaction vessel equipped with a magnetic stir bar. Then, organic solvent THF (1 mL) was added and the mixture was stirred at room temperature for complexation for 10 minutes. Finally, 1-chloro-2-(pent-4-en-1-ynyl)benzene (0.2 mmol) was added and the reaction was carried out at room temperature for 1 hour. After the reaction was completed, the reaction mixture was separated by column chromatography using n-hexane as the eluent. The solvent was removed by rotary evaporation and dried to finally obtain 26.7 mg of pure compound Ⅲ-8 with a yield of 76% and Z / E greater than 20:1.

[0153] 1 1H NMR (400 MHz, CDCl3) δ (isom Z) 7.44–7.40 (m, 1H), 7.37–7.33 (m, 1H), 7.19–7.14 (m, 2H), 6.07 (dq, J = 10.7, 6.9 Hz, 1H), 5.70 (m, 1H), 1.96 (dd, J = 6.9, 1.7 Hz, 3H).

[0154] Example 24

[0155] Under a nitrogen atmosphere, MesCu (0.01 mmol, 5 mol%), (R,R)-Ph-BPE (0.01 mmol, 5 mol%) and t-BuOH (0.2 mmol, 1 equiv.) were added to a reaction vessel equipped with a magnetic stir bar. Then, organic solvent THF (1 mL) was added and the mixture was stirred at room temperature for complexation for 10 minutes. Finally, 4-bromo-2-(pent-4-en-1-ynyl)benzene (0.2 mmol) was added and the reaction was carried out at room temperature for 1 hour. After the reaction was completed, the reaction mixture was separated by column chromatography using n-hexane as the eluent. The solvent was removed by rotary evaporation and dried to finally obtain 33.9 mg of pure compound Ⅲ-9 with a yield of 77% and Z / E greater than 20:1.

[0156] 11H NMR (400 MHz, CDCl3) δ (isom Z) 7.42–7.38 (m, 2H), 7.29–7.25 (m, 2H), 6.09–5.99 (m, 1H), 5.65 (m, 1H), 1.92 (dd, J = 6.9, 1.7 Hz, 3H).

[0157] Example 25

[0158] Under a nitrogen atmosphere, MesCu (0.01 mmol, 5 mol%), (R,R)-Ph-BPE (0.01 mmol, 5 mol%) and t-BuOH (0.2 mmol, 1 equiv.) were added to a reaction vessel equipped with a magnetic stir bar. Then, the organic solvent THF (1 mL) was added and stirred at room temperature for complexation for 10 minutes. Finally, 4-trifluoromethyl-2-(pent-4-en-1-ynyl)benzene (0.2 mmol) was added and the reaction was carried out at room temperature for 1 hour. After the reaction was completed, the reaction mixture was separated by column chromatography using n-hexane as the eluent, the solvent was removed by rotary evaporation and dried. Finally, 24.3 mg of pure compound Ⅲ-10 was obtained with a yield of 58% and Z / E greater than 20:1.

[0159] 1 1H NMR (400 MHz, CDCl3) δ (isom Z) 7.51 (m, 4H), 6.13–6.03 (m, 1H), 5.67 (dq, J = 10.7, 1.6 Hz, 1H), 1.94 (dd, J = 6.9, 1.7 Hz, 3H).

[0160] Example 26

[0161] Under a nitrogen atmosphere, MesCu (0.01 mmol, 5 mol%), (R,R)-Ph-BPE (0.01 mmol, 5 mol%) and t-BuOH (0.2 mmol, 1 equiv.) were added to a reaction vessel equipped with a magnetic stir bar. Then, the organic solvent THF (1 mL) was added and stirred at room temperature for complexation for 10 minutes. Finally, 1-(pent-4-en-1-ynyl)cyclohex-1-ene (0.2 mmol) was added and the reaction was carried out at room temperature for 1 hour. After the reaction was completed, the reaction mixture was separated by column chromatography using n-hexane as the eluent, the solvent was removed by rotary evaporation and dried. Finally, 24.1 mg of pure compound Ⅲ-11 was obtained with a yield of 82.5% and Z / E greater than 20:1.

[0162] 11H NMR (400 MHz, CDCl3) δ (isom Z) 5.93–5.81 (m, 1H), 5.54 (dd, J=10.7, 1.3 Hz, 1H), 1.84–1.79 (m, 5H), 1.54 (m, 2H).

[0163] Example 27

[0164] Under a nitrogen atmosphere, MesCu (0.01 mmol, 5 mol%), (R,R)-Ph-BPE (0.01 mmol, 5 mol%) and t-BuOH (0.2 mmol, 1 equiv.) were added to a reaction vessel equipped with a magnetic stir bar. Then, the organic solvent THF (1 mL) was added and stirred at room temperature for complexation for 10 minutes. Finally, tert-butyldimethyl(4-penten-1-yn-1-yl)silane (0.2 mmol) was added and the reaction was carried out at room temperature for 1 hour. After the reaction was completed, the reaction mixture was separated by column chromatography using n-hexane as the eluent, and the solvent was removed by rotary evaporation and dried. Finally, 32.8 mg of pure compound III-12 was obtained with a yield of 91% and Z / E greater than 20:1.

[0165] 1 1H NMR (400 MHz, CDCl3) 6.04–5.91 (m, 1H), 5.51–5.42 (m, 1H), 1.88–1.83 (m, 3H), 0.91 (s, 9H), 0.09 (s, 6H).

[0166] Example 28

[0167] Under a nitrogen atmosphere, MesCu (0.01 mmol, 5 mol%), (R,R)-Ph-BPE (0.01 mmol, 5 mol%) and t-BuOH (0.2 mmol, 1 equiv.) were added to a reaction vessel equipped with a magnetic stir bar. Then, the organic solvent THF (1 mL) was added and stirred at room temperature for complexation for 10 minutes. Finally, 1-(4-penten-1-ynyl)-3-fluorobenzene (0.2 mmol) was added and the reaction was carried out at room temperature for 1 hour. After the reaction was completed, the reaction mixture was separated by column chromatography using n-hexane as the eluent, and the solvent was removed by rotary evaporation and dried. Finally, 13.2 mg of pure compound III-13 was obtained with a yield of 41% and Z / E greater than 20:1.

[0168] 1H NMR (400 MHz, CDCl3) 7.26–7.16 (m, 2H), 7.03–6.92 (m, 2H), 6.09–5.99 (m, 1H), 5.67–5.61 (m, 1H), 1.94–1.90 (m, 3H).

[0169] The embodiments described above are only descriptions of the preferred embodiments of the present invention, and do not limit the scope of the present invention. Without departing from the design spirit of the present invention, various deformations and improvements made by those of ordinary skill in the art to the technical solutions of the present invention shall fall within the protection scope determined by the claims of the present invention.

Claims

1. A method for the copper-catalyzed synthesis of 1,3-enyne compounds, characterized in that, Under a protective atmosphere, using the 1,4-enyne compound shown in Formula I as a substrate, MesCu as a catalyst, Xantphos as a ligand, methanol as an additive, and tetrahydrofuran as a solvent, react at -25 to 25 °C for 1 to 5 hours, and then separate and purify to obtain the trans-1,3-enyne shown in Formula II; Among them, R1 is a substituted or unsubstituted aromatic ring, heteroaromatic ring, and alkyl substituent; substitution includes mono- to trisubstitution, and the substituents are selected from tert-butyl, methoxy, halogen, halogen-substituted alkyl, cyano, aryl, substituted aryl, or silyl; R2, R3, and R4 are all H or alkyl, halogen, halogen-substituted alkyl, cyano, or trifluoromethyl.

2. The method for copper-catalyzed synthesis of 1,3-enyne compounds according to claim 1, wherein When preparing the trans-1,3-enyne shown in Formula II: Under a protective atmosphere, using the 1,4-enyne compound shown in Formula I as a substrate, MesCu as a catalyst, Xantphos as a non-chiral ligand for constructing the trans-1,3-enyne, methanol as an additive, and tetrahydrofuran as a solvent, react at -25 to 25 °C for 1 to 5 hours, and then separate and purify.

3. The method for copper-catalyzed synthesis of 1,3-enyne compounds according to claim 2, characterized in that, When preparing the trans-1,3-enyne shown in Formula II, the following steps are included: 1) Under nitrogen protection, add the catalyst MesCu, the non-chiral ligand Xantphos, the additive methanol, and the solvent tetrahydrofuran to the reaction vessel, and complex and stir at room temperature for 10 minutes; 2) Add the 1,4-enyne compound as the substrate shown in Formula I, and react at -25 to 25 °C for 1 to 5 h; 3) After the reaction is completed, perform column chromatography separation, the eluent is n-hexane, collect the eluate of the target compound, remove the solvent and dry it to finally obtain the trans-1,3-enyne shown in Formula II.

4. The method for catalytically synthesizing 1,3-enyne compounds with copper according to claim 3, characterized in that, When preparing the trans-1,3-enyne shown in Formula II, the amount of the catalyst MesCu used is 1 to 20% of the molar amount of the 1,4-enyne compound; The amount of the non-chiral ligand Xantphos used is 1 to 20% of the molar amount of the 1,4-enyne compound; The amount of the additive methanol used is 0.5 to 2 times the molar amount of the 1,4-enyne compound.

5. A method for the copper-catalyzed synthesis of 1,3-enyne compounds according to claim 1, characterized in that, The structural formula of the 1,4-enyne compound is as follows: 。 6. A method for the copper-catalyzed synthesis of 1,3-enyne compounds, characterized in that, Under a protective atmosphere, using the 1,4-enyne compound as a substrate, MesCu as a catalyst, Xantphos as a ligand, methanol as an additive, and tetrahydrofuran as a solvent, react at -25 to 25 °C for 1 to 5 hours, and then separate and purify to obtain the trans-1,3-enyne shown in Formula II; The structural formula of the 1,4-enyne compound is as follows: , , , , , , , or .

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