A mechanically assisted allylic site selective oxidation method

Abstract

The present invention discloses a method for mechanically assisted allylic selective oxidation, which relates to the technical field of selective oxidation of organic compounds. The method comprises the following steps: mixing a metal-ligand complex, a base, 2,2,6,6-tetramethylpiperidine oxide and its derivatives, a solvent and a reaction substrate, and then carrying out a reaction under the action of mechanical external force to achieve allylic selective oxidation and obtain an allylic selectively oxidized product. The present invention adopts an S-Phos / Ag catalytic oxidation system to achieve the construction of a fully hydrocarbon backbone regio- and stereoselective oxidation reaction without the participation of a reducing agent, without using expensive palladium as a catalyst, and avoiding the generation of a large amount of chemical waste. The present invention selects ball milling mechanochemistry to replace the traditional solution system, avoiding the use of a large amount of organic solvents, with less waste discharge, resource conservation, environmental friendliness, high atom utilization rate, and having the characteristics of simple operation, short reaction time and high efficiency, which is beneficial to industrial-scale preparation.

Description

Technical Field

[0001] The present invention relates to the technical field of selective oxidation of organic compounds, and particularly to a method for mechanically assisted allylic selective oxidation. Background Art

[0002] Selective oxidation reactions are one of the most widely applied reaction types in academic research and industry, and significant progress has been made in the selective oxidation of C-H bonds to C-O bonds catalyzed by transition metals. However, the above methods have the following limitations: 1) narrow substrate scope; 2) use of expensive palladium as a catalyst or require more than equivalent amounts of reducing agents, resulting in high costs and the generation of palladium-containing waste; 3) relatively harsh reaction conditions, complex operations, and cumbersome steps; 4) difficult to control E / Z (cis-trans isomers belong to a type of stereoisomer. Cis-trans isomers with the same molecular formula but different structural formulas generally have obvious differences in physical, chemical, and biological properties. For example, the two configurations of the non-steroidal anti-estrogen tamoxifen have completely opposite pharmacological effects. Its Z-isomer has anti-estrogenic effects, while the E-isomer is an estrogen stimulant.); 5) low reaction yields.

[0003] Transition metal-catalyzed selective oxidation of C-H bonds to C-O bonds provides an efficient and convenient synthetic route for the construction of C-O bonds. One special type of C-O bond construction is the α-hydroxylation reaction of olefins to form allyl alcoholates, and the resulting product structures are widely used in drug synthesis. The α-hydroxy structure can further undergo oxidation, substitution, etc. reactions to generate corresponding active pharmaceutical ingredients and chemical intermediates. For example, it can be used for the efficient synthesis of aspartic acid diol derivatives (anti-tumor), small molecule candidate drugs NNC 61-4655 for the treatment of type II diabetes, allylamine antifungal drug terbinafine (Lamisil, produced by Novartis, Switzerland) and Oxamflatin (a new low-toxic histone deacetylase with anti-cancer cell proliferation and deacetylation inhibition effects), as well as Naftifine (naftifine, a broad-spectrum allylamine antifungal drug, clinically used for the treatment of skin fungal infections), etc.

[0004] The structures of bioactive molecules containing allyl alcoholate or its α-hydroxy derivative structural fragments are as follows:

[0005]

[0006] How to overcome the limitations of the method for selectively oxidizing C-H bonds to C-O bonds catalyzed by transition metals is a technical problem that urgently needs to be solved in the technical field of selective oxidation of organic compounds. Summary of the Invention

[0007] Based on the above, the present invention provides a mechanically-assisted allylic selective oxidation method, which has the advantages of a wide substrate scope, no need to use expensive palladium as a catalyst or a reducing agent in an amount equivalent to or more than the equivalent, simple operation, and high yield.

[0008] To achieve the above object, the present invention provides the following solutions:

[0009] One of the technical solutions of the present invention is an allylic selective oxidation method, which includes the following steps: mixing a metal-ligand complex, a base, 2,2,6,6-tetramethylpiperidine oxide and its derivatives, a solvent, and a reaction substrate, and then reacting under mechanical external force to achieve allylic selective oxidation and obtain an allylic selective oxidation product;

[0010] The metal-ligand complex is [AgBF4·(Ligand) x , where x = 1 to 2;

[0011] The purpose of preparing the metal and the ligand into a complex is, on the one hand, convenient operation and easy storage, and on the other hand, compared with simply adding AgBF4 and S-Phos to the reaction system in a molar ratio, the metal-ligand complex can improve the yield of the final product.

[0012] The reaction substrate is a 1,4-enyne or an olefin compound;

[0013] The 2,2,6,6-tetramethylpiperidine oxide and its derivatives are one of 2,2,6,6-tetramethylpiperidine oxide (TEMPO) or its derivatives.

[0014] The 2,2,6,6-tetramethylpiperidine oxide and its derivatives are one of the following structures:

[0015]

[0016] The structural formula of the ligand in the metal-ligand complex is one of the following structural formulas.

[0017]

[0018] When the reaction substrate is a 1,4-enyne compound, the reaction process is as follows:

[0019]

[0020] When the reaction substrate is an olefin compound, the reaction process is as follows:

[0021]

[0022] Further, the molar ratio of the metal-ligand complex, the base, 2,2,6,6-tetramethylpiperidine-N-oxide and its derivatives to the reaction substrate is preferably 0.1:2:1.5:1 to 1:4:3:2; the volume-mass ratio of the amount of the solvent to the total amount of all raw materials except the solvent is: 1 μL: 1-6 mg.; the reaction time is 0 to 3 h and not 0, and more preferably, the reaction time is 1 h.

[0023] If the parameter ratio and the reaction time exceed the above-mentioned range, although the reaction product can be obtained, there will be problems such as waste of resources such as materials and equipment, reduction of atom utilization rate, and increase of cost.

[0024] Further, the base is one of cesium carbonate (Cs2CO3), potassium carbonate (K2CO3) and tetramethylguanidine (TMG), and preferably cesium carbonate; the solvent is one of tetrahydrofuran, 2-methyltetrahydrofuran, ethyl acetate, toluene, cyclohexane, n-hexane, n-pentane, cyclopentane and diethyl ether, and preferably cyclohexane or diethyl ether.

[0025] Other common bases such as sodium hydroxide and potassium hydroxide cannot achieve the technical effects of the present invention, cannot produce the final product, or the yield of the final product is extremely low.

[0026] Further, the structural formula of the reaction substrate is one of the following structural formulas:

[0027]

[0028] Further, the preparation method of the [AgBF4·(Ligand) x comprises the following steps:

[0029] Dissolve silver tetrafluoroborate and 2-dicyclohexylphosphino-2′,6′-dimethoxy-biphenyl in a solvent, and then remove the solvent by rotary evaporation to obtain the [AgBF4·(Ligand) x .

[0030] Further, the equivalent ratio of silver tetrafluoroborate to 2-dicyclohexylphosphino-2′,6′-dimethoxy-biphenyl is 1:1 to 2, and preferably 1:2; the solvent is a mixed solution of dichloromethane and tetrahydrofuran with a volume ratio of 2:1.

[0031] Further, the mechanical external force is applied by placing the mixed material in a ball mill and grinding it at a frequency of 10 to 35 Hz; preferably, the frequency is 35 Hz.

[0032] If the frequency is too low, the reaction yield will drop significantly. At present, a frequency of 35 Hz can already achieve a high yield, so there is no need to further increase the frequency.

[0033] Furthermore, after the reaction is completed, it also includes the steps of eluting from silica gel, removing the solvent by vacuum distillation, and purifying the crude product by silica gel column chromatography.

[0034] The second technical solution of the present invention is a method for broadening the substrate applicability range in the allylic selective oxidation process, which adopts the above-mentioned allylic selective oxidation method.

[0035] The third technical solution of the present invention is a method for avoiding the generation of palladium-containing waste in the allylic selective oxidation process, which adopts the above-mentioned allylic selective oxidation method.

[0036] The fourth technical solution of the present invention is a method for increasing the product yield in the allylic selective oxidation process, which adopts the above-mentioned allylic selective oxidation method.

[0037] The present invention discloses the following technical effects:

[0038] The present invention adopts the S-Phos / Ag catalytic oxidation system to achieve the construction of a regio- and stereoselective (reflected by the E / Z ratio of the product, that is, cis-trans isomerism) oxidation reaction of the all-carbon hydrogen skeleton without the participation of a reducing agent, without using expensive palladium as a catalyst, avoiding the generation of a large amount of chemical waste, and meeting the increasing requirements for green chemistry.

[0039] The present invention selects ball-milling mechanochemistry to replace the traditional solution system, avoiding the use of a large amount of organic solvents, with less waste discharge, resource conservation, environmental friendliness, high atom utilization rate, and the method of the present invention is simple to operate, has a short reaction time, high efficiency, and is conducive to industrial-scale preparation.

[0040] Only a small amount of analytical pure solvent is used in the reaction process of the present invention, the solvent consumption is small, and the use of ultra-dry solvent is avoided, greatly reducing the cost, and the method of the present invention can obtain a high yield under air conditions, is simple to operate, and is suitable for industrial scale-up.

[0041] The final product prepared by the method of the present invention has a high yield and good E / Z control. Detailed Description of the Invention

[0042] 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 embodiments of the present invention.

[0043] It should be understood that the terms used 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. Each 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.

[0044] Unless otherwise specified, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this 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.

[0045] 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's specification, which will be obvious to those skilled in the art. Other embodiments obtained from the specification of the present invention will be obvious to those skilled in the art. The specification and examples of this application are merely exemplary.

[0046] Regarding the use of "comprising", "including", "having", "containing", etc. in this article, they are all open-ended terms, meaning including but not limited to.

[0047] The preparation method of AgBF4·(Ligand)2 used in the embodiments of the present invention is specifically as follows: Silver tetrafluoroborate and 2-dicyclohexylphosphino-2′,6′-dimethoxy-biphenyl (S-Phos) are placed in a 100 mL round-bottom flask in an equivalent ratio of 1:2, 30 mL of dichloromethane and 15 mL of tetrahydrofuran are added to completely dissolve them, and the solvent is removed using a rotary evaporator to obtain a white solid, namely AgBF4·(Ligand)2, for standby.

[0048] Example 1

[0049]

[0050] The synthesis steps are as follows:

[0051] AgBF4·(Ligand)2 (0.1 mmol, 20.3 mg, 10 mol%), cesium carbonate (0.4 mmol, 130.3 mg, 2.0 eq.), TEMPO (0.3 mmol, 46.9 mg, 1.5 eq.), cyclohexane (50.0 μL), and 1,4-enyne substrate (0.2 mmol, 28.4 mg, 1.0 eq.) were added to a 1.5 mL stainless steel vial (containing a stainless steel ball with a diameter of 6 mm). The stainless steel vial was tightened and placed on a ball mill for grinding (Retsch MM500, 35 Hz, 60 minutes). After grinding, the mixture was eluted from the silica gel with ethyl acetate, and the solvent was removed by distillation under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate, 100:0 - 10:1), and 44.6 mg of yellow oily liquid was collected and dried, with a yield of 75.0% and E:Z = 4.1:1.

[0052] 1 1H NMR (400 MHz, CDCl3) (isom E) δ 7.46–7.41 (dd, J = 6.7, 3.1 Hz, 2H), 7.33–7.29 (dd, J = 5.1, 2.0 Hz, 3H), 6.31–6.22 (dt, J = 15.9, 5.2 Hz, 1H), 6.02–5.95 (dt, J = 16.0, 2.0 Hz, 1H), 4.41–4.38 (dd, J = 5.3, 2.0 Hz, 2H), 1.49–1.44 (m, 4H), 1.43–1.18 (m, 2H), 1.18–1.12 (d, J = 17.8 Hz, 12H).

[0053] 13 13C NMR (101 MHz, CDCl3) (isom E) δ 139.2, 131.5, 128.3, 128.1, 123.3, 110.3, 89.6, 87.8, 59.8, 39.6, 32.9, 20.1, 17.0.

[0054] 1 1H NMR (400 MHz, CDCl3) (isom Z) δ 7.43–7.38 (m, 2H), 7.33–7.29 (m, 3H), 6.14–6.06 (dt, J = 11.0, 6.6 Hz, 1H), 5.82–5.76 (dt, J = 10.9, 1.5 Hz, 1H), 4.66–4.61 (dd, J = 6.6, 1.5 Hz, 2H), 1.50–1.44 (dd, J = 8.1, 4.5 Hz, 4H), 1.43–1.25 (m, 2H), 1.24–1.10 (d, J = 47.5 Hz, 12H).

[0055] HRMS(ESI)Calcd.For C 20 H 28 NO:298.21654([M+H] + ).Found:298.21614.

[0056] Comparative Example 1

[0057] The difference from Example 1 is only that the ball milling treatment is replaced by static reaction, that is, after tightening the stainless steel tank, the static reaction is carried out for 60 minutes.

[0058] The results show that no E and Z configuration products are finally formed.

[0059] Example 2:

[0060]

[0061] Its synthesis steps are as follows:

[0062] AgBF4·(Ligand)2(0.1 mmol, 20.3 mg, 10 mol%), cesium carbonate (0.4 mmol, 130.3 mg, 2.0 eq.), TEMPO (0.3 mmol, 46.9 mg, 1.5 eq.), cyclohexane (50.0 μL), 1,4-enyne substrate (0.2 mmol, 29.2 mg, 1.0 eq.) were added to a 1.5 mL stainless steel tank (containing a stainless steel ball with a diameter of 6 mm), the stainless steel tank was tightened, and placed on a ball mill for grinding (Retsch MM500, 35 Hz, 60 minutes). After the grinding was completed, the mixture was eluted from the silica gel with ethyl acetate, the solvent was removed by distillation under reduced pressure, and the crude product was purified by silica gel column chromatography (the eluent was n-hexane / ethyl acetate, 100:0 - 10:1). 43.2 mg of yellow oily liquid was collected and dried, with a yield of 71.6%, E:Z = 4.5:1.

[0063] 1 H NMR(400 MHz, CDCl3)(isomE)δ6.23–6.03(m, 2H), 5.91–5.81(dt, J = 15.9, 1.9 Hz, 1H), 4.36–4.30(dd, J = 5.5, 1.9 Hz, 2H), 2.17–2.06(m, 4H), 1.69–1.53(m, 5H), f1.56–1.36(dd, J = 8.9, 2.9 Hz, 4H), 1.36–1.23(m, 1H), 1.17–1.06(d, J = 18.1 Hz, 12H).

[0064] 1313C NMR (101 MHz, CDCl3) (isomE) δ 137.9, 134.8, 120.7, 110.8, 91.6, 85.1, 59.8, 39.6, 32.9, 29.1, 25.7, 22.3, 21.5, 20.1, 17.1.

[0065] 1 1H NMR (400 MHz, CDCl3) (isomZ) δ 6.11–6.06 (m, 1H), 6.01–5.93 (dt, J = 10.8, 6.6 Hz, 1H), 5.71–5.65 (d, J = 10.9 Hz, 1H), 4.56–4.52 (dd, J = 6.6, 1.5 Hz, 2H), 2.14–2.09 (dt, J = 6.3, 3.0 Hz, 4H), 1.67–1.58 (m, 5H), 1.40–1.35 (s, 1H), 1.21–1.09 (d, J = 41.7 Hz, 12H).

[0066] Example 3:

[0067]

[0068] The synthesis steps are as follows:

[0069] AgBF4·(Ligand)2 (0.1 mmol, 20.3 mg, 10 mol%), cesium carbonate (0.4 mmol, 130.3 mg, 2.0 eq.), TEMPO (0.3 mmol, 46.9 mg, 1.5 eq.), cyclohexane (50.0 μL), and 1,4-enyne substrate (0.2 mmol, 36.1 mg, 1.0 eq.) were added to a 1.5 mL stainless steel jar (containing a stainless steel ball with a diameter of 6 mm). The stainless steel jar was tightened and placed on a ball mill for grinding (Retsch MM500, 35 Hz, 60 minutes). After grinding, the mixture was eluted from the silica gel with ethyl acetate, and the solvent was removed by distillation under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate, 100:0 - 10:1). 44.8 mg of yellow oily liquid was collected and dried, with a yield of 66.7%, E:Z = 5.0:1.

[0070] 11H NMR (400 MHz, CDCl3) (isomE) δ 6.23–6.03 (m, 2H), 5.91–5.81 (dt, J = 15.9, 1.9 Hz, 1H), 4.36–4.30 (dd, J = 5.5, 1.9 Hz, 2H), 2.17–2.06 (m, 4H), 1.69–1.53 (m, 5H), 1.56–1.36 (dd, J = 8.9, 2.9 Hz, 4H), 1.36–1.23 (m, 1H), 1.17–1.06 (d, J = 18.1 Hz, 12H).

[0071] 1 1H NMR (400 MHz, CDCl3) (isomZ) δ 6.15–6.00 (dt, J = 11.0, 6.7 Hz, 1H), 5.64–5.52 (m, 1H), 4.60–4.53 (dd, J = 6.6, 1.6 Hz, 2H), 1.49–1.41 (d, J = 7.2 Hz, 4H), 1.32–1.24 (m, 2H), 1.21–1.06 (d, J = 38.2 Hz, 12H), 0.98–0.87 (s, 9H), 0.23– -0.01 (s, 6H).

[0072] Example 4:

[0073]

[0074] The synthesis steps are as follows:

[0075] AgBF4·(Ligand)2 (0.1 mmol, 20.3 mg, 10 mol%), cesium carbonate (0.4 mmol, 130.3 mg, 2.0 eq.), TEMPO (0.3 mmol, 46.9 mg, 1.5 eq.), cyclohexane (50.0 μL), and 1,4-enyne substrate (0.2 mmol, 31.2 mg, 1.0 eq.) were added to a 1.5 mL stainless steel vial (containing a 6 mm diameter stainless steel ball). The stainless steel vial was tightened and placed on a ball mill for grinding (Retsch MM500, 35 Hz, 60 minutes). After grinding, the mixture was eluted from the silica gel with ethyl acetate, and the solvent was removed by distillation under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate, 100:0 - 10:1). The yellow oily liquid (44.4 mg) was collected and dried, with a yield of 71.3% and E:Z = 4.4:1.

[0076] 11H NMR (400 MHz, CDCl3) (isomE) δ 7.35–7.30 (d, J = 7.9 Hz, 2H), 7.14–7.10 (d, J = 7.9 Hz, 2H), 6.28–6.20 (dt, J = 16.1, 5.3 Hz, 1H), 6.00–5.93 (dt, J = 15.9, 1.9 Hz, 1H), 4.40–4.37 (dd, J = 5.4, 1.9 Hz, 2H), 2.36–2.34 (s, 3H), 1.48–1.43 (dd, J = 8.7, 3.0 Hz, 4H), 1.41–1.22 (m, 2H), 1.18–1.11 (d, J = 18.3 Hz, 12H).

[0077] 13 13C NMR (101 MHz, CDCl3) (isomE) δ 138.8, 138.2, 131.3, 129.0, 120.2, 110.5, 89.8, 87.1, 59.8, 39.6, 32.9, 21.5, 20.1, 17.1.

[0078] 1 1H NMR (400 MHz, CDCl3) (isomZ) δ 7.33–7.28 (m, 2H), 7.13–7.10 (d, J = 7.9 Hz, 2H), 6.11–6.03 (dt, J = 10.9, 6.6 Hz, 1H), 5.80–5.75 (dt, J = 10.8, 1.5 Hz, 1H), 4.64–4.61 (dd, J = 6.6, 1.6 Hz, 2H), 2.36–2.34 (s, 3H), 1.50–1.44 (dd, J = 7.6, 4.2 Hz, 4H), 1.36–1.25 (m, 2H), 1.23–1.10 (d, J = 47.4 Hz, 12H).

[0079] Example 5:

[0080]

[0081] The synthesis steps are as follows:

[0082] AgBF4·(Ligand)2 (0.1 mmol, 20.3 mg, 10 mol%), cesium carbonate (0.4 mmol, 130.3 mg, 2.0 eq.), TEMPO (0.3 mmol, 46.9 mg, 1.5 eq.), cyclohexane (50.0 μL), and 1,4-enyne substrate (0.2 mmol, 31.2 mg, 1.0 eq.) were added to a 1.5 mL stainless steel vessel (containing a stainless steel ball with a diameter of 6 mm). The stainless steel vessel was tightened and placed on a ball mill for grinding (Retsch MM500, 35 Hz, 60 minutes). After grinding, the mixture was eluted from the silica gel with ethyl acetate, and the solvent was removed by distillation under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate, 100:0 - 10:1). The product was collected and dried to obtain 26.8 mg of a yellow oily liquid with a yield of 43.1% and E:Z = 6.0:1.

[0083] 1 H NMR (400 MHz, CDCl3) (isomE) δ 7.47–7.42 (dd, J = 7.6, 2.0 Hz, 2H), 7.34–7.28 (m, 3H), 5.86–5.80 (q, J = 1.5 Hz, 1H), 4.33–4.29 (d, J = 1.7 Hz, 2H), 1.97–1.94 (d, J = 1.1 Hz, 3H), 1.49–1.44 (m, 4H), 1.42–1.21 (m, 2H), 1.17–1.12 (d, J = 13.1 Hz, 12H).

[0084] 1 H NMR (400 MHz, CDCl3) (isomZ) δ 7.39–7.35 (m, 2H), 7.29–7.26 (dd, J = 5.9, 3.7 Hz, 3H), 5.59–5.55 (d, J = 1.8 Hz, 1H), 4.59–4.57 (s, 2H), 1.97–1.95 (d, J = 1.6 Hz, 3H), 1.50–1.44 (d, J = 13.4 Hz, 4H), 1.40–1.30 (d, J = 27.6 Hz, 2H), 1.25–1.11 (m, 12H).

[0085] Example 6:

[0086]

[0087] The synthesis steps are as follows:

[0088] AgBF4·(Ligand)2 (0.1 mmol, 20.3 mg, 10 mol%), cesium carbonate (0.4 mmol, 130.3 mg, 2.0 eq.), TEMPO (0.3 mmol, 46.9 mg, 1.5 eq.), cyclohexane (50.0 μL), and 1,4-enyne substrate (0.2 mmol, 29.6 mg, 1.0 eq.) were added to a 1.5 mL stainless steel jar (containing a stainless steel ball with a diameter of 6 mm). The stainless steel jar was tightened and placed on a ball mill for grinding (Retsch MM500, 35 Hz, 60 minutes). After grinding, the mixture was eluted from the silica gel with ethyl acetate, and the solvent was removed by distillation under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate, 100:0 - 10:1), and 18.6 mg of a yellow oily liquid was collected and dried, with a yield of 30.7% and E:Z = 4.2:1.

[0089] 1 H NMR (400 MHz, CDCl3) (isomE) δ 7.45–7.40 (d, J = 2.8 Hz, 1H), 7.28–7.24 (m, 2H), 7.12–7.08 (d, J = 4.9 Hz, 1H), 6.29–6.19 (dt, J = 16.0, 5.2 Hz, 1H), 6.00–5.90 (dt, J = 16.0, 2.0 Hz, 1H), 4.40–4.37 (dd, J = 5.2, 1.9 Hz, 2H), 1.47–1.43 (m, 4H), 1.43–1.17 (m, 2H), 1.17–1.11 (d, J = 17.7 Hz, 12H).

[0090] 1 H NMR (400 MHz, CDCl3) (isomZ) δ 7.42–7.39 (d, J = 2.9 Hz, 1H), 7.28–7.25 (m, 1H), 7.11–7.06 (dd, J = 4.9, 1.1 Hz, 1H), 6.13–6.04 (dt, J = 10.9, 6.6 Hz, 1H), 5.79–5.73 (dt, J = 10.9, 1.6 Hz, 1H), 4.64–4.59 (dd, J = 6.5, 1.5 Hz, 2H), 1.49–1.44 (dd, J = 7.9, 4.3 Hz, 4H), 1.40–1.25 (m, 2H), 1.23–1.10 (d, J = 46.0 Hz, 12H).

[0091] Example 7:

[0092]

[0093] The synthesis steps are as follows:

[0094] AgBF4·(Ligand)2 (0.1 mmol, 20.3 mg, 10 mol %), cesium carbonate (0.4 mmol, 130.3 mg, 2.0 eq.), TEMPO (0.3 mmol, 46.9 mg, 1.5 eq.), cyclohexane (50.0 μL), and cinnamene (0.2 mmol, 26.1 μL, 1.0 eq.) were added to a 1.5 mL stainless steel jar (containing a stainless steel ball with a diameter of 6 mm). The stainless steel jar was tightened and placed on a ball mill for grinding (Retsch MM500, 35 Hz, 60 minutes). After grinding, the mixture was eluted from the silica gel with ethyl acetate, and the solvent was removed by distillation under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate, 100:0 - 10:1). 7.8 mg of yellow oily liquid was collected and dried, with a yield of 14.3% and E:Z > 20.

[0095] 1 H NMR (400 MHz, CDCl3) (isomE) δ 7.45–7.40 (d δ 7.42–7.38 (m, 2H), 7.34–7.28 (dd, J = 8.3, 6.6 Hz, 2H), 7.25–7.20 (m, 1H), 6.64–6.56 (dt, J = 16.0, 1.7 Hz, 1H), 6.34–6.25 (dt, J = 15.9, 5.9 Hz, 1H), 4.47–4.43 (dd, J = 6.0, 1.6 Hz, 2H), 1.51–1.44 (dd, J = 7.2, 3.9 Hz, 4H), 1.43–1.22 (dq, J = 12.6, 3.3 Hz, 2H), 1.23–1.12 (d, J = 30.8 Hz, 12H).

[0096] Example 8:

[0097]

[0098] The synthesis steps are as follows:

[0099] AgBF4·(Ligand)2 (0.1 mmol, 20.3 mg, 10 mol%), cesium carbonate (0.4 mmol, 130.3 mg, 2.0 eq.), TEMPO (0.3 mmol, 46.9 mg, 1.5 eq.), cyclohexane (50.0 μL), and 1,4-enyne substrate (0.2 mmol, 27.7 mg, 1.0 eq.) were added to a 1.5 mL stainless steel autoclave (containing a stainless steel ball with a diameter of 6 mm). The stainless steel autoclave was tightened and placed on a ball mill for grinding (Retsch MM500, 35 Hz, 60 minutes). After grinding, the mixture was eluted from the silica gel with ethyl acetate, and the solvent was removed by distillation under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate, 100:0 - 10:1). The product was collected and dried to obtain 32.5 mg of a yellow oily liquid with a yield of 55.4% and E:Z = 4.6:1.

[0100] 1 1H NMR (400 MHz, CDCl3) (isom E) δ 6.26–6.18 (dt, J = 16.1, 5.0 Hz, 1H), 5.82–5.75 (dt, J = 16.0, 2.1 Hz, 1H), 4.34–4.31 (dd, J = 5.0, 2.0 Hz, 2H), 1.46–1.42 (dd, J = 9.1, 3.3 Hz, 4H), 1.41–1.14 (m, 2H), 1.13–1.08 (d, J = 14.7 Hz, 12H), 0.19–0.18 (s, 9H).

[0101] 1 1H NMR (400 MHz, CDCl3) (isom Z) δ 6.10–6.02 (dt, J = 11.0, 6.7 Hz, 1H), 5.63–5.55 (dt, J = 11.0, 1.5 Hz, 1H), 4.59–4.51 (dd, J = 6.8, 1.5 Hz, 2H), 1.48–1.43 (m, 4H), 1.40–1.24 (dd, J = 33.9, 21.6 Hz, 2H), 1.21–1.09 (d, J = 41.0 Hz, 12H), 0.18–0.16 (s, 9H).

[0102] Example 9:

[0103]

[0104] The synthesis steps are as follows:

[0105] AgBF4·(Ligand)2 (0.1 mmol, 20.3 mg, 10 mol%), cesium carbonate (0.4 mmol, 130.3 mg, 2.0 eq.), TEMPO (0.3 mmol, 46.9 mg, 1.5 eq.), cyclohexane (50.0 μL), and 1,4-enyne substrate (0.2 mmol, 38.5 mg, 1.0 eq.) were added to a 1.5 mL stainless steel vial (containing a stainless steel ball with a diameter of 6 mm). The stainless steel vial was tightened and placed on a ball mill for grinding (Retsch MM500, 35 Hz, 60 minutes). After grinding, the mixture was eluted from the silica gel with ethyl acetate, and the solvent was removed by distillation under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate, 100:0 - 10:1). The product was collected and dried to obtain 14.4 mg of a yellow oily liquid with a yield of 20.8% and E:Z = 4.5:1.

[0106] 1 H NMR (400 MHz, CDCl3) (isomE) δ 7.97–7.93 (d, J = 1.6 Hz, 1H), 7.82–7.76 (m, 3H), 7.50–7.46 (m, 3H), 6.36–6.26 (dt, J = 16.0, 5.2 Hz, 1H), 6.07–5.98 (dt, J = 15.9, 2.0 Hz, 1H), 4.44–4.40 (dd, J = 5.2, 1.9 Hz, 2H), 1.49–1.44 (dd, J = 9.1, 2.8 Hz, 4H), 1.38–1.22 (m, 2H), 1.19–1.13 (d, J = 18.2 Hz, 12H).

[0107] 1 H NMR (400 MHz, CDCl3) (isomZ) δ 7.94–7.92 (s, 1H), 7.82–7.76 (td, J = 9.0, 8.3, 6.4 Hz, 3H), 7.51–7.44 (m, 3H), 6.17–6.09 (dt, J = 11.0, 6.6 Hz, 1H), 5.86–5.81 (dt, J = 10.8, 1.6 Hz, 1H), 4.72–4.67 (dd, J = 6.6, 1.5 Hz, 2H), 1.53–1.46 (d, J = 7.7 Hz, 4H), 1.43–1.29 (dd, J = 29.1, 6.7 Hz, 2H), 1.26–1.12 (d, J = 52.9 Hz, 12H).

[0108] Example 10:

[0109]

[0110] The synthesis steps are as follows:

[0111] AgBF4·(Ligand)2 (0.1 mmol, 20.3 mg, 10 mol%), cesium carbonate (0.4 mmol, 130.3 mg, 2.0 eq.), TEMPO (0.3 mmol, 46.9 mg, 1.5 eq.), cyclohexane (50.0 μL), and 1,4-enyne substrate (0.2 mmol, 31.2 mg, 1.0 eq.) were added to a 1.5 mL stainless steel jar (containing a stainless steel ball with a diameter of 6 mm). The stainless steel jar was tightened and placed on a ball mill for grinding (Retsch MM500, 35 Hz, 60 minutes). After grinding, the mixture was eluted from the silica gel with ethyl acetate, and the solvent was removed by distillation under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate, 100:0 - 10:1). 36.2 mg of yellow oily liquid was collected and dried, with a yield of 58.1%, and E:Z = 4.5:1.

[0112] 1 H NMR (400 MHz, CDCl3) (isomE) δ 7.25–7.14 (m, 4H), 7.11–7.05 (d, J = 7.4 Hz, 1H), 6.27–6.18 (dt, J = 15.9, 5.2 Hz, 1H), 5.98–5.90 (dt, J = 16.1, 2.0 Hz, 1H), 4.38–4.34 (dd, J = 5.2, 1.9 Hz, 2H), 2.31–2.29 (s, 3H), 1.46–1.41 (dd, J = 9.1, 2.9 Hz, 4H), 1.41–1.15 (m, 2H), 1.15–1.08 (d, J = 17.8 Hz, 12H).

[0113] 13 C NMR (101 MHz, CDCl3) (isomE) δ 139.0, 137.9, 132.0, 128.9, 128.5, 128.1, 123.1, 110.4, 89.7, 87.4, 59.8, 39.6, 32.8, 21.2, 20.1, 17.0.

[0114] 11H NMR (400 MHz, CDCl3) (isomZ) δ 7.24–7.16 (m, 3H), 7.13–7.09 (dd, J = 6.9, 1.9 Hz, 1H), 6.11–6.04 (dt, J = 11.0, 6.6 Hz, 1H), 5.80–5.74 (dt, J = 11.0, 1.6 Hz, 1H), 4.64–4.61 (dd, J = 6.6, 1.5 Hz, 2H), 2.33–2.31 (s, 3H), 1.50–1.43 (dd, J = 8.2, 4.7 Hz, 4H), 1.43–1.24 (m, 2H), 1.23–1.08 (d, J = 47.6 Hz, 12H).

[0115] Example 11:

[0116]

[0117] The synthesis steps are as follows:

[0118] AgBF4·(Ligand)2 (0.1 mmol, 20.3 mg, 10 mol%), cesium carbonate (0.4 mmol, 130.3 mg, 2.0 eq.), TEMPO (0.3 mmol, 46.9 mg, 1.5 eq.), cyclohexane (50.0 μL), 1,4-enyne substrate (0.2 mmol, 32.0 mg, 1.0 eq.) were added to a 1.5 mL stainless steel tank (containing a stainless steel ball with a diameter of 6 mm). The stainless steel tank was tightened and placed on a ball mill for grinding (Retsch MM500, 35 Hz, 60 minutes). After grinding, the mixture was eluted from the silica gel with ethyl acetate, and the solvent was removed by distillation under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate, 100:0 - 10:1). 31.4 mg of yellow oily liquid was collected and dried, with a yield of 49.8%, E:Z = 4.3:1.

[0119] 11H NMR (400 MHz, CDCl3) (isomE) δ 7.31–7.23 (m, 3H), 7.23–7.18 (m, 1H), 7.15–7.08 (dt, J = 9.4, 2.1 Hz, 1H), 7.04–6.97 (td, J = 8.5, 2.7 Hz, 1H), 6.32–6.24 (dt, J = 16.0, 5.1 Hz, 1H), 6.00–5.92 (dt, J = 16.0, 2.0 Hz, 1H), 4.43–4.36 (dd, J = 5.1, 2.0 Hz, 2H), 1.48–1.43 (dd, J = 9.3, 3.0 Hz, 4H), 1.42–1.21 (m, 2H), 1.17–1.11 (d, J = 16.4 Hz, 12H).

[0120] 19 19F NMR (376 MHz, CDCl3) (isomE) δ -113.0

[0121] 1 1H NMR (400 MHz, CDCl3) (isomZ) δ 7.31–7.24 (m, 1H), 7.21–7.17 (d, J = 7.7 Hz, 1H), 7.12–7.07 (dt, J = 9.5, 2.1 Hz, 1H), 7.05–6.98 (td, J = 8.5, 2.8 Hz, 1H), 6.17–6.09 (dt, J = 11.0, 6.6 Hz, 1H), 5.80–5.74 (dd, J = 10.9, 1.7 Hz, 1H), 4.65–4.59 (dd, J = 6.6, 1.6 Hz, 2H), 1.50–1.44 (m, 4H), 1.41–1.26 (m, 2H), 1.23–1.09 (d, J = 45.6 Hz, 12H).

[0122] 19 19F NMR (376 MHz, CDCl3) (isomZ) δ -112.9.

[0123] Example 12:

[0124]

[0125] The synthesis steps are as follows:

[0126] AgBF4·(Ligand)2 (0.1 mmol, 20.3 mg, 10 mol%), cesium carbonate (0.4 mmol, 130.3 mg, 2.0 eq.), TEMPO (0.3 mmol, 46.9 mg, 1.5 eq.), cyclohexane (50.0 μL), and 1,4-enyne substrate (0.2 mmol, 31.2 mg, 1.0 eq.) were added to a 1.5 mL stainless steel vessel (containing a stainless steel ball with a diameter of 6 mm). The stainless steel vessel was tightened and placed on a ball mill for grinding (Retsch MM500, 35 Hz, 60 minutes). After grinding, the mixture was eluted from the silica gel with ethyl acetate, and the solvent was removed by distillation under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate, 100:0 - 10:1), and 53.2 mg of a yellow oily liquid was collected and dried, with a yield of 85.4% and E:Z = 4.7:1.

[0127] 1 H NMR (400 MHz, CDCl3) (isomE) δ 7.43–7.37 (d, J = 7.5 Hz, 1H), 7.22–7.18 (d, J = 3.9 Hz, 2H), 7.17–7.10 (dq, J = 8.6, 4.4 Hz, 1H), 6.30–6.21 (dt, J = 15.9, 5.2 Hz, 1H), 6.05–5.98 (dt, J = 16.1, 2.1 Hz, 1H), 4.43–4.37 (dd, J = 5.2, 1.9 Hz, 2H), 2.45–2.43 (s, 3H), 1.49–1.44 (dd, J = 9.3, 2.8 Hz, 4H), 1.42–1.20 (m, 2H), 1.19–1.12 (d, J = 17.8 Hz, 12H).

[0128] 13 C NMR (101 MHz, CDCl3) (isomE) δ 140.0, 138.7, 131.7, 129.3, 128.0, 125.4, 123.1, 110.6, 91.6, 88.5, 59.8, 39.6, 32.8, 20.6, 20.1, 17.0.

[0129] 11H NMR (400 MHz, CDCl3) (isomZ) δ 7.41–7.37 (d, J = 7.5 Hz, 1H), 7.22–7.18 (m, J = 5.1 Hz, 2H), 7.16–7.10 (m, J = 8.6, 5.5, 3.1 Hz, 1H), 6.14–6.06 (dt, J = 11.0, 6.5 Hz, 1H), 5.85–5.79 (dt, J = 11.0, 1.8 Hz, 1H), 4.69–4.64 (dd, J = 6.6, 1.6 Hz, 2H), 2.44–2.42 (s, 3H), 1.49–1.44 (m, 4H), 1.40–1.23 (m, 2H), 1.22–1.10 (d, J = 42.0 Hz, 12H).

[0130] Example 13:

[0131]

[0132] The synthesis steps are as follows:

[0133] AgBF4·(Ligand)2 (0.1 mmol, 20.3 mg, 10 mol%), cesium carbonate (0.4 mmol, 130.3 mg, 2.0 eq.), TEMPO (0.3 mmol, 46.9 mg, 1.5 eq.), cyclohexane (50.0 μL), and 1,4-enyne substrate (0.2 mmol, 32.0 mg, 1.0 eq.) were added to a 1.5 mL stainless steel tank (containing a stainless steel ball with a diameter of 6 mm). The stainless steel tank was tightened and placed on a ball mill for grinding (Retsch MM500, 35 Hz, 60 minutes). After grinding, the mixture was eluted from the silica gel with ethyl acetate, and the solvent was removed by distillation under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate, 100:0 - 10:1). The yellow oily liquid (31.4 mg) was collected and dried, with a yield of 65.6%, and E:Z = 4.1:1.

[0134] 1 1H NMR (400 MHz, CDCl3) (isomE) δ 7.42–7.37 (m, 2H), 7.02–6.96 (t, J = 8.7 Hz, 2H), 6.29–6.20 (dt, J = 16.0, 5.1 Hz, 1H), 5.98–5.90 (m, 1H), 4.40–4.36 (dd, J = 5.2, 2.0 Hz, 2H), 1.46–1.42 (dd, J = 9.2, 3.0 Hz, 4H), 1.41–1.18 (m, 2H), 1.16–1.10 (d, J = 17.4 Hz, 12H).

[0135] 13 13C NMR (101 MHz, CDCl3) (isomE) δ 163.5, 161.0, 139.3, 133.3, 133.2, 115.6, 115.4, 88.4, 87.4, 59.8, 39.5, 32.8, 20.1, 17.0.

[0136] 19 19F NMR (376 MHz, CDCl3) (isomE) δ -111.1.

[0137] 1 1H NMR (400 MHz, CDCl3) (isomZ) δ 7.43–7.35 (m, 2H), 7.03–6.96 (m, 2H), 6.17–6.05 (dt, J=10.9, 6.6 Hz, 1H), 5.84–5.71 (dt, J=10.9, 1.6 Hz, 1H), 4.69–4.57 (dd, J=6.6, 1.6 Hz, 2H), 1.50–1.44 (dd, J=7.7, 4.2 Hz, 4H), 1.40–1.24 (m, 2H), 1.23–1.10 (d, J=45.4 Hz, 12H).

[0138] 19 19F NMR (376 MHz, CDCl3) (isomZ) δ -110.9.

[0139] Example 14:

[0140]

[0141] The synthesis steps are as follows:

[0142] AgBF4·(Ligand)2 (0.1 mmol, 20.3 mg, 10 mol%), cesium carbonate (0.4 mmol, 130.3 mg, 2.0 eq.), TEMPO (0.3 mmol, 46.9 mg, 1.5 eq.), cyclohexane (50.0 μL), and 1,4-enyne substrate (0.2 mmol, 44.2 mg, 1.0 eq.) were added to a 1.5 mL stainless steel tank (containing a stainless steel ball with a diameter of 6 mm). The stainless steel tank was tightened and placed on a ball mill for grinding (Retsch MM500, 35 Hz, 60 minutes). After grinding, the mixture was eluted from the silica gel with ethyl acetate, and the solvent was removed by distillation under reduced pressure. The crude product was purified by silica column chromatography (eluent: n-hexane / ethyl acetate, 100:0 - 10:1). 51.7 mg of white powdery solid was collected and dried, with a yield of 68.7% and E:Z = 4.1:1.

[0143] 1 1H NMR (400 MHz, CDCl3) (isomE) δ 7.45–7.40 (m, 2H), 7.29–7.25 (m, 2H), 6.30–6.21 (dt, J = 15.9, 5.0 Hz, 1H), 5.98–5.90 (dt, J = 16.0, 2.1 Hz, 1H), 4.40–4.36 (dd, J = 5.1, 2.0 Hz, 2H), 1.47–1.42 (dd, J = 9.1, 3.1 Hz, 4H), 1.41–1.16 (m, 2H), 1.15–1.08 (d, J = 16.7 Hz, 12H).

[0144] 13 13C NMR (101 MHz, CDCl3) (isomE) δ 139.8, 132.9, 131.5, 122.2, 109.9, 88.9, 88.5, 59.9, 39.6, 32.8, 20.1, 17.0.

[0145] 1 1H NMR (400 MHz, CDCl3) (isomZ) δ 7.47–7.42 (m, 2H), 7.29–7.24 (d, J = 8.5 Hz, 12H), 6.17–6.08 (dt, J = 10.9, 6.6 Hz, 1H), 5.80–5.73 (dt, J = 11.0, 1.6 Hz, 1H), 4.65–4.59 (dd, J = 6.6, 1.6 Hz, 2H), 1.33–1.25 (m, 2H), 1.23–1.10 (d, J = 44.2 Hz, 12H).

[0146] Example 15:

[0147]

[0148] The synthesis steps are as follows:

[0149] AgBF4·(Ligand)2 (0.1 mmol, 20.3 mg, 10 mol%), cesium carbonate (0.4 mmol, 130.3 mg, 2.0 eq.), TEMPO (0.3 mmol, 46.9 mg, 1.5 eq.), cyclohexane (50.0 μL), and 1,4-enyne substrate (0.2 mmol, 42.0 mg, 1.0 eq.) were added to a 1.5 mL stainless steel vial (containing a stainless steel ball with a diameter of 6 mm). The stainless steel vial was tightened and placed on a ball mill for grinding (Retsch MM500, 35 Hz, 60 minutes). After grinding, the mixture was eluted from the silica gel with ethyl acetate, and the solvent was removed by distillation under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate, 100:0 - 10:1), and 25.5 mg of yellow oily liquid was collected and dried, with a yield of 34.9%, E:Z = 4.9:1.

[0150] 1 H NMR (400 MHz, CDCl3) (isomE) δ 7.58–7.50 (q, J = 8.4 Hz, 4H), 6.37–6.26 (dt, J = 16.1, 5.0 Hz, 1H), 6.02–5.95 (dt, J = 16.0, 2.1 Hz, 1H), 4.43–4.39 (dd, J = 4.9, 2.0 Hz, 2H), 1.48–1.43 (dd, J = 9.0, 3.2 Hz, 4H), 1.42–1.19 (m, 2H), 1.17–1.12 (d, J = 15.9 Hz, 12H).

[0151] 19 F NMR (376 MHz, CDCl3) (isomE) δ -62.69.

[0152] 1 H NMR (400 MHz, CDCl3) (isomZ) δ 7.59–7.49 (m, 4H), 6.22–6.12 (dt, J = 11.0, 6.6 Hz, 1H), 5.82–5.76 (dt, J = 11.0, 1.6 Hz, 1H), 4.65–4.60 (dd, J = 6.6, 1.6 Hz, 2H), 1.49–1.45 (m, 4H), 1.39–1.26 (m, 2H), 1.23–1.10 (d, J = 44.8 Hz, 12H).

[0153] 19 F NMR (376 MHz, CDCl3) (isomZ) δ -62.66.

[0154] Example 16:

[0155]

[0156] The synthesis steps are as follows:

[0157] Add AgBF4·(Ligand)2 (0.1 mmol, 20.3 mg, 10 mol%), cesium carbonate (0.4 mmol, 130.3 mg, 2.0 eq.), TEMPO (0.3 mmol, 46.9 mg, 1.5 eq.), cyclohexane (50.0 μL), and 1,4-enyne substrate (0.2 mmol, 35.2 mg, 1.0 eq.) into a 1.5 mL stainless steel tank (containing a stainless steel ball with a diameter of 6 mm). Tighten the stainless steel tank and place it on a ball mill for grinding (Retsch MM500, 35 Hz, 60 minutes). After grinding, the mixture is eluted from the silica gel with ethyl acetate, the solvent is removed by distillation under reduced pressure, and the crude product is purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate, 100:0 - 10:1). Collect and dry to obtain a yellow oily liquid with a yield of 15%.

[0158] 1 H NMR (400 MHz, CDCl3) (isomE) δ 7.38–7.33 (m, 2H), 7.29–7.27 (s, 2H), 6.30–6.22 (dt, J = 16.0, 5.1 Hz, 1H), 6.00–5.93 (m, 1H), 4.43–4.37 (dd, J = 5.2, 2.0 Hz, 2H), 1.47–1.43 (dd, J = 8.9, 3.2 Hz, 4H), 1.26–1.24 (m, 2H), 1.17–1.11 (d, J = 16.7 Hz, 12H).

[0159] Example 17:

[0160]

[0161] The synthesis steps are as follows:

[0162] AgBF4·(Ligand)2 (0.1 mmol, 20.3 mg, 10 mol%), cesium carbonate (0.4 mmol, 130.3 mg, 2.0 eq.), TEMPO (0.3 mmol, 46.9 mg, 1.5 eq.), cyclohexane (50.0 μL), and 1,4-enyne substrate (0.2 mmol, 34.1 mg, 1.0 eq.) were added to a 1.5 mL stainless steel autoclave (containing a stainless steel ball with a diameter of 6 mm). The stainless steel autoclave was tightened and placed on a ball mill for grinding (Retsch MM500, 35 Hz, 60 minutes). After grinding, the mixture was eluted from the silica gel with ethyl acetate, and the solvent was removed by distillation under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate, 100:0 - 10:1). The product was collected and dried to obtain 8.7 mg of a yellow oily liquid with a yield of 13.3% and E:Z = 3.7:1.

[0163] 1 H NMR (400 MHz, CDCl3) (isomE) δ 7.32–7.28 (d, J = 7.2 Hz, 2H), 7.24–7.21 (d, J = 7.4 Hz, 3H), 6.13–6.02 (dt, J = 16.0, 5.4 Hz, 1H), 5.76–5.66 (dp, J = 15.8, 2.0 Hz, 1H), 4.33–4.28 (dd, J = 5.3, 1.9 Hz, 2H), 2.89–2.81 (t, J = 7.6 Hz, 2H), 2.62–2.56 (td, J = 7.6, 2.1 Hz, 2H), 1.47–1.42 (dd, J = 8.9, 3.0 Hz, 4H), 1.33–1.21 (m, 2H), 1.14–1.09 (d, J = 17.5 Hz, 12H).

[0164] 1 H NMR (400 MHz, CDCl3) (isomZ) δ 7.30–7.28 (d, J = 7.3 Hz, 2H), 7.23–7.21 (d, J = 7.0 Hz, 3H), 6.01–5.92 (m, 1H), 5.58–5.49 (m, 1H), 4.57–4.48 (dd, J = 6.3, 1.6 Hz, 2H), 2.86–2.82 (m, 2H), 2.63–2.59 (m, 2H), 1.47–1.44 (d, J = 6.8 Hz, 4H), 1.36–1.26 (d, J = 19.6 Hz, 2H), 1.19–1.09 (d, J = 37.7 Hz, 12H).

[0165] The structural fragment of 2-ene-4-yne-1-ol is an intermediate widely used in pharmaceutical synthesis and can be used for the efficient synthesis of drugs or drug candidates such as aspartic acid diol derivatives (anti-tumor) and allylamine antifungal drugs (terbinafine). For example, the E-form product in Example 1 of the present invention can generate the product of (E)-5-phenylpent-2-ene-4-yne-1-ol under the action of acetic acid, zinc, and THF at 70 °C, and then synthesize the anti-diabetic drug candidate NNC 61-4655.

[0166] The above embodiments 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 allylic selective oxidation, characterized in that, It includes the following steps: Mix a metal-ligand complex, a base, 2,2,6,6-tetramethylpiperidine N-oxide, solvent A, and a reaction substrate, and then carry out a reaction under mechanical external force to achieve allylic selective oxidation of the reaction substrate and obtain an allylic selectively oxidized product; The metal-ligand complex is [AgBF4•(Ligand) x , where x = 2; The reaction substrate is a 1,4-enyne compound or an olefin compound, and the structural formula is one of the following structural formulas: ； The base is one of cesium carbonate, potassium carbonate, and tetramethylguanidine; the solvent A is one of tetrahydrofuran, 2-methyltetrahydrofuran, ethyl acetate, toluene, cyclohexane, n-hexane, n-pentane, cyclopentane, and diethyl ether; The preparation method of [[AgBF4•(Ligand)]] x comprises the following steps: Silver tetrafluoroborate and 2-dicyclohexylphosphino-2′,6′-dimethoxy-biphenyl were added to solvent B for dissolution, and then solvent B was removed by rotary evaporation to obtain the [AgBF4•(Ligand) x ; The mechanical external force is applied by sealing the mixed material and placing it in a ball mill for grinding at a frequency of 10 - 35 Hz; When the reaction substrate is a 1,4-enyne compound, the reaction process is as follows: ； When the reaction substrate is an olefin compound, the reaction process is as follows: ； The Ligand structural formula in [[AgBF4•(Ligand)]] x is as follows: 。 2. The allylic selective oxidation method according to claim 1, characterized in that, The molar ratio of the metal-ligand complex, the base, 2,2,6,6-tetramethylpiperidine N-oxide to the reaction substrate is 0.1:2:1.5:1 to 1:4:3:2; the volume-mass ratio of the amount of solvent A used to the total amount of all raw materials except solvent A is: 1 μL: 1 - 6 mg; the reaction time is 0 - 3 h and is not 0.

3. The allylic selective oxidation method according to claim 1, characterized in that, The equivalent ratio of silver tetrafluoroborate and 2-dicyclohexylphosphino-2′,6′-dimethoxy-biphenyl is 1:1 to 2; the solvent B is a mixed solution of dichloromethane and tetrahydrofuran with a volume ratio of 2:

1.

4. A method for broadening the substrate applicability range in the allylic selective oxidation process, characterized in that, Use the allylic selective oxidation method described in claim 1.

5. A method for avoiding the generation of palladium-containing waste during allylic selective oxidation, characterized in that, Use the allylic selective oxidation method described in claim 1.

6. A method for improving the product yield in the allylic selective oxidation process, characterized in that, Use the allylic selective oxidation method described in claim 1.

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