A copper-catalyzed synthesis method of trifluoromethyl allene compounds

Abstract

The invention discloses a method for synthesizing a copper-catalyzed trifluoromethyl allene compound, and belongs to the field of organic allene chemical synthesis. The invention uses trifluoromethyl reagent TogniII, aromatic olefins, and aromatic alkynes as raw materials, copper salts as catalysts, α, α, α-terpyridine as ligands, adds potassium carbonate, reacts at room temperature for 24 hours in a mixed solvent of acetonitrile and methanol, and obtains a trifluoromethylated allene compound after the reaction is completed. The synthesis method catalyst and reaction raw materials of the invention are simple and easy to obtain, the reaction conditions are mild, the functional group compatibility is good, the operation is convenient, and there is a good industrial application prospect.

Description

Technical Field

[0001] The invention belongs to the field of organic allene chemical synthesis, and in particular relates to a method for synthesizing a trifluoromethyl allene compound using copper catalysis. Background Art

[0002] The introduction of trifluoromethyl into organic molecules can enhance the lipid solubility, metabolic stability, antioxidant properties and rigidity of the molecules. Trifluoromethyl compounds are widely used in medicine, pesticides, and advanced materials. Therefore, chemists have been attracted to conduct research on the synthesis of organic compounds containing trifluoromethyl functional groups.

[0003] Allene compounds are not only widely used in bioactive molecules, natural products and drug molecules, but also as important intermediates in organic reactions, they are widely used in organic chemical synthesis. In the past few decades, the preparation of allene compounds has aroused the research interest of organic chemists and medicinal chemists.

[0004] There are literatures (Org. Lett., 2015, 17, 2506; Org. Lett., 2016, 18, 5162; Chem. Commun., 2013, 49, 7809) reporting that trifluoromethyl biacetylene compounds can react with Cu-CF 3 Direct coupling synthesis of complexes, this method requires the participation of strong base reagents and high temperature conditions. In recent years, there are literatures (Chin. J. Chem., 2020, 38, 91) reporting that free radical-mediated 1,4 addition of 1,3-enyne compounds is used as a powerful strategy for the efficient and convenient preparation of polyfluorinated substituted allenes. However, this reaction strategy requires the pre-preparation of 1,3-enyne compounds, and the reaction steps are cumbersome. Summary of the invention

[0005] The purpose of the present invention is to provide a copper-catalyzed synthesis method of trifluoromethyl allene compounds, the catalyst and raw materials of the method are cheap and easy to obtain, the reaction efficiency is high, the adaptability of the functional group is good, the reaction conditions are mild, the operation is simple, and the method has good industrial application prospects.

[0006] A method for copper-catalyzed synthesis of trifluoromethylated allene compounds, comprising the following steps:

[0007] Using copper salt as catalyst, α, α, α-terpyridine as ligand, Togni II trifluoromethyl reagent, aromatic alkynes and aromatic olefins as raw materials, potassium carbonate as base, in a mixed solvent of methanol and acetonitrile with a solvent ratio of 7:3, the trifluoromethylated allene compound was prepared by reaction;

[0008] The structural formula of the trifluoromethylated allene compound is: The structural formula of the TogniII trifluoromethyl reagent is: The structural formula of the olefin is: The structural formula of the alkyne is:

[0009] Among them, Ar 1 ,Ar 2 is a substituted or unsubstituted aromatic ring, a substituted or unsubstituted aromatic heterocycle; substitution includes one to three substitutions, and the substituents are selected from: C1-8 alkyl, C1-8 alkoxy, halogen (F, Cl, Br, I), and halogen-substituted C1-8 alkyl.

[0010] In one embodiment of the present invention, the reaction temperature is room temperature (20-30° C.) and the reaction time is 24 hours.

[0011] In one embodiment of the present invention, the aromatic ring is a benzene ring or a naphthalene ring.

[0012] In one embodiment of the present invention, the aromatic heterocycle is a 5-membered or 6-membered aromatic heterocycle, a 5-membered or 6-membered benzo aromatic heterocycle, and has at least one heteroatom selected from N, S, and O. Specific options include:

[0013] In one embodiment of the present invention, the ligand comprises any one or more of the following structures:

[0014] R 1 Selected from H, C1-4 alkyl.

[0015] In one embodiment of the present invention, R 1 Specifically, it may be H(α,α,α--terpyridine).

[0016] In one embodiment of the present invention, the method according to claim 1 is characterized in that the molar ratio of the aromatic olefin compound, the aromatic alkyne compound, and the Togni II trifluoromethyl reagent is 1:1.5:1.5.

[0017] In one embodiment of the present invention, the amount of the ligand relative to the aromatic olefin compound is 20 mol%.

[0018] In one embodiment of the present invention, the amount of the copper salt relative to the aromatic olefin compound is 10 mol%.

[0019] In one embodiment of the present invention, the copper salt is selected from any one or more of the following: Cu(OAc) 2 , Cul, and Cu(OTf) 2 Specifically, Cu(OTf) is preferred. 2 .

[0020] In one embodiment of the present invention, the alkaline reagent includes any one or more of the following: K 3 PO 4 、Na 2 CO 3 , K 2 CO 3 and Et 3 N. Specifically preferred is K 2 CO 3 .

[0021] In one embodiment of the present invention, the molar ratio of the alkaline agent to the aromatic olefin compound is 3:1.

[0022] In one embodiment of the present invention, the organic solvent is methanol, or a mixed solvent of methanol and acetonitrile. When a mixed solvent of methanol and acetonitrile is selected, the mixed volume ratio is 7:3.

[0023] In one embodiment of the present invention, the amount of the organic solvent used is 1 mL / 0.2 mmol of the aromatic olefin compound reagent, that is, 5 mL / mmol of the aromatic olefin compound.

[0024] In one embodiment of the present invention, the reaction is carried out under an inert atmosphere.

[0025] In one embodiment of the present invention, the synthetic route of the reaction is as follows:

[0026]

[0027] In one embodiment of the present invention, Ar 1 ,Ar 2 The substitution in the definition specifically includes: mono-substitution, tri-substitution; the positions of multiple substitutions can be selected as ortho, meta, or para; the substituents can be selected as: -Me, -OMe, -Ph, -F, -Cl, -Br, -CF 3 、-COOMe.

[0028] In one embodiment of the present invention, the trifluoromethylated allene compound specifically comprises the following structure:

[0029]

[0030]

[0031] In one embodiment of the present invention, the method comprises the following specific steps:

[0032] In a reaction tube with a stirrer, N 2Under the atmosphere, catalyst, ligand, aromatic olefin compound, aromatic alkyne compound, Tongni II trifluoromethyl reagent, base, methanol, acetonitrile were added in sequence and stirred at room temperature for 24 hours. After the reaction was completed, the reaction mixture was filtered through diatomaceous earth, washed with ethyl acetate, the organic phases were combined, and the solvent was removed by rotary evaporator to obtain a crude product, which was separated by silica gel column chromatography using petroleum ether and ethyl acetate as eluents to finally obtain the target compound.

[0033] Beneficial effects:

[0034] The invention uses trifluoromethyl reagent Togni II, aromatic olefins, and aromatic alkynes as raw materials, copper salt as a catalyst, α, α, α-terpyridine as a ligand, adds potassium carbonate, reacts in a mixed solvent of acetonitrile and methanol at room temperature for 24 hours, and obtains a trifluoromethylated allene compound after the reaction is completed. The synthesis method of the invention has simple and easy-to-obtain catalysts and reaction raw materials, mild reaction conditions, good functional group compatibility, convenient operation, and good industrial application prospects. BRIEF DESCRIPTION OF THE DRAWINGS

[0035] Figure 1 The schematic diagram of the synthesis method of the present invention is shown in FIG. DETAILED DESCRIPTION

[0036] In order to make the contents of the present invention easier to understand, the technical solution of the present invention is further described below in conjunction with specific implementation methods, but the present invention is not limited to the scope of the embodiments.

[0037] Example 1

[0038] In a reaction tube with a stirrer, under N2 atmosphere, the catalyst Cu(OTf) was added in sequence. 2 (0.02mmol, 10mol%), ligand α, α, a-terpyridine (0.04mmol, 20mol%), p-methylstyrene (0.2mmol, 1equiv), phenylacetylene (0.3mmol, 1.5equiv), TongniII trifluoromethyl reagent (0.2mmol, 1equiv), potassium carbonate (0.6mmol, 3equiv), methanol solvent (0.7mL), acetonitrile solvent (0.3mL), stirred at room temperature for 24h. After the reaction is completed, the reaction mixture is filtered through diatomaceous earth, rinsed with ethyl acetate, the organic phases are combined, and the solvent is removed by a rotary evaporator to obtain a crude product, which is separated by silica gel column chromatography, using petroleum ether and ethyl acetate as eluents, and finally obtaining a compound of formula 1 (isolation yield 79%).

[0039]

[0040] 1 H NMR (400 MHz, CDCl 3 )δ7.40-7.35(m, 6H), 7.31-7.25(m, 1H), 7.19(d, J=8.0Hz, 2H), 6.66(s, 1H), 7.47-7.33(m, 2H), 2.37(s, 3H); 13 C NMR (101 MHz, CDCl 3 ) δ208.5, 137.5, 133.1, 131.5, 129.4, 128.8, 127.6, 127.2, 125.9 (d, J=277.5Hz), 125.9, 100.2 (q, J=3.1Hz), 98.5, 35.3 (q, J=29.7Hz), 21.1; 19 F NMR (376 MHz, CDCl 3 )δ-64.5.

[0041] Example 2

[0042] In a reaction tube with a stirrer, N 2 Under the atmosphere, catalyst Cu(OTf) was added successively 2 (0.02mmol, 10mol%), ligand α, α, α-terpyridine (0.04mmol, 20mol%), p-tert-butylstyrene (0.2mmol, 1equiv), phenylacetylene (0.3mmol, 1.5equiv), TongniII trifluoromethyl reagent (0.2mmol, 1equiv), potassium carbonate (0.6mmol, 3equiv), methanol solvent (0.7mL), acetonitrile solvent (0.3mL), stirred at room temperature for 24h. After the reaction is completed, the reaction mixture is filtered through diatomaceous earth, rinsed with ethyl acetate, the organic phases are combined, and the solvent is removed by a rotary evaporator to obtain a crude product, which is separated by silica gel column chromatography, using petroleum ether and ethyl acetate as eluents, and finally obtaining a compound of formula 2 (isolation yield 79%).

[0043]

[0044] 1 H NMR (400 MHz, CDCl 3 )δ7.43-7.32(m, 8H), 7.27(dd, J=8.7, 5.1Hz, 1H), 6.66(s, 1H), 3.50-3.29(m, 2H), 1.34(s, 9H); 13 C NMR (101 MHz, CDCl 3)δ208.6, 150.8, 133.1, 131.4, 128.8, 127.6, 127.2, 125.9 (d, J=277.5Hz) , 125.7, 125.7, 100.0 (q, J=3.2Hz), 98.6, 35.3 (q, J=29.7Hz), 34.5, 31.2; 19 F NMR (376 MHz, CDCl 3 )δ-64.5.

[0045] Example 3

[0046] In a reaction tube with a stirrer, N 2 Under the atmosphere, catalyst Cu(OTf) was added successively 2 (0.02mmol, 10mol%), ligand α,α,α-terpyridine (0.04mmol, 20mol%), m-methylstyrene (0.2mmol, 1equiv), phenylacetylene (0.3mmol, 1.5equiv), TongniII trifluoromethyl reagent (0.2mmol, 1equiv), potassium carbonate (0.6mmol, 3equiv), methanol solvent (0.7mL), acetonitrile solvent (0.3mL), stirred at room temperature for 24h. After the reaction is completed, the reaction mixture is filtered through diatomaceous earth, rinsed with ethyl acetate, the organic phases are combined, and the solvent is removed by a rotary evaporator to obtain a crude product, which is separated by silica gel column chromatography, using petroleum ether and ethyl acetate as eluents, and finally obtaining a compound of formula 3 (isolation yield 80%).

[0047]

[0048] 1 H NMR (400 MHz, CDCl 3 )67.42-7.34(m, 4H), 7.30-7.26(m, 4H), 7.12-7.10(m, 1H), 6.67(s, 1H), 3.49-3.28(m, 2H), 2.37(s, 3H); 13 C NMR (101 MHz, CDCl 3 )δ208.6, 138.4, 134.4, 133.0, 128.8, 128.6, 128.5, 127.7, 127.2, 126.7, 125 .9 (q, J=277.5Hz), 123.1, 100.3 (q, J=3.1Hz), 98.5, 35.4 (q, J=29.7Hz), 21.5; 19 F NMR (376 MHz, CDCl 3 )δ-64.5.

[0049] Example 4

[0050] In a reaction tube with a stirrer, N 2 Under the atmosphere, catalyst Cu(OTf) was added successively 2 (0.02mmol, 10mol%), ligand α, α, α-terpyridine (0.04mmol, 20mol%), distyrene (0.2mmol, 1equiv), phenylacetylene (0.3mmol, 1.5equiv), TongniII trifluoromethyl reagent (0.2mmol, 1equiv), potassium carbonate (0.6mmol, 3equiv), methanol solvent (0.7mL), acetonitrile solvent (0.3mL), stirred at room temperature for 24h. After the reaction is completed, the reaction mixture is filtered through diatomaceous earth, rinsed with ethyl acetate, the organic phases are combined, and the solvent is removed by a rotary evaporator to obtain a crude product, which is separated by silica gel column chromatography, using petroleum ether and ethyl acetate as eluents, and finally obtaining a compound of formula 4 (isolation yield 63%).

[0051]

[0052] 1 H NMR (400 MHz, CDCl 3 )δ7.65-7.58 (m, 4H), 7.53 (d, J=8.4Hz, 2H), 7.46 (t, J=7.6Hz, 2H), 7.43-7.35 (m, 5H), 7.29 (t, J=6.9Hz, 1H), 6.71 (s, 1H), 3.52-3.35 (m, 2H); 13 CNMR (101MHz, CDCl 3 )δ209.0, 140.5, 140.4, 133.3, 132.8, 128.9, 128.8, 127.8, 127.5, 127.4, 127.2, 1 27.0, 126.4, 125.9 (q, J=277.4Hz), 100.1 (q, J=3.0Hz), 98.8, 35.3 (q, J=29.7Hz); 19 F NMR (376 MHz, CDCl 3 )δ-64.4.

[0053] Example 5

[0054] In a reaction tube with a stirrer, N 2 Under the atmosphere, catalyst Cu(OTf) was added successively 2(0.02mmol, 10mol%), ligand α,α,α-terpyridine (0.04mmol, 20mol%), p-fluorostyrene (0.2mmol, 1equiv), phenylacetylene (0.3mmol, 1.5equiv), TongniII trifluoromethyl reagent (0.2mmol, 1equiv), potassium carbonate (0.6mmol, 3equiv), methanol solvent (0.7mL), acetonitrile solvent (0.3mL), stirred at room temperature for 24h. After the reaction is completed, the reaction mixture is filtered through diatomaceous earth, rinsed with ethyl acetate, the organic phases are combined, and the solvent is removed by a rotary evaporator to obtain a crude product, which is separated by silica gel column chromatography, using petroleum ether and ethyl acetate as eluents, and finally obtaining a compound of formula 5 (isolation yield 61%).

[0055]

[0056] 1 H NMR (400 MHz, CDCl 3 )δ7.43-7.32(m, 6H), 7.30-7.25(m, 1H), 7.04(t, J=8.6Hz, 2H), 6.65(s, 1H), 3.45-3.27(m, 2H); 13 C NMR (101 MHz, CDCl 3 )δ208.5 (d, J=1.5Hz), 162.3 (d, J=247.5Hz), 132.7, 130.5 (d, J=3.5Hz), 128.8, 127.8, 127.7 (d, J=8. 1Hz), 127.2, 125.8 (q, J=277.8Hz), 115.7 (d, J=21.8Hz), 99.5 (q, J=3.3Hz), 98.7, 35.6 (q, J=29.8Hz); 19 F NMR (376 MHz, CDCl 3 )δ-64.4, -114.5.

[0057] Example 6

[0058] In a reaction tube with a stirrer, N 2 Under the atmosphere, catalyst Cu(OTf) was added successively 2(0.02mmol, 10mol%), ligand α, α, α-terpyridine (0.04mmol, 20mol%), p-chlorostyrene (0.2mmol, 1equiv), phenylacetylene (0.3mmol, 1.5equiv), TongniII trifluoromethyl reagent (0.2mmol, 1equiv), potassium carbonate (0.6mmol, 3equiv), methanol solvent (0.7mL), acetonitrile solvent (0.3mL), stirred at room temperature for 24h. After the reaction is completed, the reaction mixture is filtered through diatomaceous earth, rinsed with ethyl acetate, the organic phases are combined, and the solvent is removed by a rotary evaporator to obtain a crude product, which is separated by silica gel column chromatography, using petroleum ether and ethyl acetate as eluents, and finally obtaining a compound of formula 6 (isolation yield 52%).

[0059]

[0060] 1 H NMR (400 MHz, CDCl 3 )δ7.54-7.25(m, 9H), 6.70(s, 1H), 3.47-3.29(m, 2H); 13 CNMR (101MHz, CDCl 3 )δ208.8, 133.5, 133.0, 132.5, 128.9, 128.9, 127.9, 127.3, 127.2, 125.7 (q, J=277.6Hz), 99.6 (q, J=3.4Hz), 98.9, 35.3 (q, J=29.9Hz); 19 F NMR (376 MHz, CDCl 3 )δ-64.5.

[0061] Example 7

[0062] In a reaction tube with a stirrer, N 2 Under the atmosphere, catalyst Cu(OTf) was added successively 2(0.02mmol, 10mol%), ligand α,α,α-terpyridine (0.04mmol, 20mol%), p-bromostyrene (0.2mmol, 1equiv), phenylacetylene (0.3mmol, 1.5equiv), TongniII trifluoromethyl reagent (0.2mmol, 1equiv), potassium carbonate (0.6mmol, 3equiv), methanol solvent (0.7mL), acetonitrile solvent (0.3mL), stirred at room temperature for 24h. After the reaction is completed, the reaction mixture is filtered through diatomaceous earth, rinsed with ethyl acetate, the organic phases are combined, and the solvent is removed by a rotary evaporator to obtain a crude product, which is separated by silica gel column chromatography, using petroleum ether and ethyl acetate as eluents, and finally obtaining a compound of formula 7 (isolation yield 43%).

[0063]

[0064] 1 H NMR (400 MHz, CDCl 3 )δ7.50-7.43(m, 2H), 7.35(d, J=4.3Hz, 4H), 7.31-7.25(m, 3H), 6.66(s, 1H), 3.44-3.26(m, 2H); 13 C NMR (101 MHz, CDCl 3 )δ208.8, 133.5, 132.4, 131.8, 128.9, 127.9, 127.6, 127.2, 125.7 (q, J=277.6Hz), 121.6, 99.6 (q, J=3.4Hz), 99.0, 35.3 (q, J=29.9Hz); 19 F NMR (376 MHz, CDCl 3 )δ-64.5.

[0065] Example 8

[0066] In a reaction tube with a stirrer, N 2 Under the atmosphere, catalyst Cu(OTf) was added successively 2(0.02mmol, 10mol%), ligand α, α, α-terpyridine (0.04mmol, 20mol%), 2-vinylnaphthalene (0.2mmol, 1equiv), phenylacetylene (0.3mmol, 1.5equiv), TongniII trifluoromethyl reagent (0.2mmol, 1equiv), potassium carbonate (0.6mmol, 3equiv), methanol solvent (0.7mL), acetonitrile solvent (0.3mL), stirred at room temperature for 24h. After the reaction is completed, the reaction mixture is filtered through diatomaceous earth, rinsed with ethyl acetate, the organic phases are combined, and the solvent is removed by a rotary evaporator to obtain a crude product, which is separated by silica gel column chromatography, using petroleum ether and ethyl acetate as eluents, and finally obtaining a compound of formula 8 (isolation yield 64%).

[0067]

[0068] 1 H NMR (400 MHz, CDCl 3 )δ7.88-7.76(m, 4H), 7.61(dd, J=8.7, 1.8Hz, 1H), 7.54-7.46(m, 2H), 7.43-7.35(m, 4H), 7.32-7.26(m, 1H), 6.75(s, 1H), 3.61-3.44(m, 2H); 13 C NMR (101 MHz, CDCl 3 )δ209.3, 133.5, 132.9, 132.7, 131.8, 128.9, 128.3, 128.1, 127.8, 127.6, 127.3, 126.4, 1 26.2, 125.9 (q, J=277.5Hz), 124.7, 124.1, 100.5 (q, J=3.2Hz), 99.0, 35.3 (q, J=29.8Hz); 19 F NMR (376 MHz, CDCl 3 )δ-64.3.

[0069] Example 9

[0070] In a reaction tube with a stirrer, N 2 Under the atmosphere, catalyst Cu(OTf) was added successively 2(0.02mmol, 10mol%), ligand α, α, α-terpyridine (0.04mmol, 20mol%), styrene (0.2mmol, 1equiv), p-methylphenylacetylene (0.3mmol, 1.5equiv), TongniII trifluoromethyl reagent (0.2mmol, 1equiv), potassium carbonate (0.6mmol, 3equiv), methanol solvent (0.7mL), acetonitrile solvent (0.3mL), stirred at room temperature for 24h. After the reaction is completed, the reaction mixture is filtered through diatomaceous earth, rinsed with ethyl acetate, the organic phases are combined, and the solvent is removed by a rotary evaporator to obtain a crude product, which is separated by silica gel column chromatography, using petroleum ether and ethyl acetate as eluents, and finally obtaining a compound of formula 9 (isolation yield 70%).

[0071]

[0072] 1 H NMR (400 MHz, CDCl 3 )δ7.44 (d, J=7.7Hz, 2H), 7.35 (t, J=7.6Hz, 2H), 7.30-7.25 (m, 3H), 7.16 (d, J=7.9Hz, 2H), 6.65 (s, 1H), 3.48-3.26 (m, 2H), 2.36 (s, 3H); 13 C NMR (101 MHz, CDCl 3 )δ208.6, 137.6, 134.7, 132.4, 129.6, 128.7, 127.5, 127.1, 126.0, 125.9 (q, J=277.5Hz), 100.1 (q, J=3.1Hz), 98.4, 35.3 (q, J=29.7Hz), 21.2; 19 F NMR (376 MHz, CDCl 3 )δ-64.5.

[0073] Example 10

[0074] In a reaction tube with a stirrer, N 2 Under the atmosphere, catalyst Cu(OTf) was added successively 2(0.02mmol, 10mol%), ligand α, α, α-terpyridine (0.04mmol, 20mol%), styrene (0.2mmol, 1equiv), m-methylphenylacetylene (0.3mmol, 1.5equiv), TongniII trifluoromethyl reagent (0.2mmol, 1equiv), potassium carbonate (0.6mmol, 3equiv), methanol solvent (0.7mL), acetonitrile solvent (0.3mL), stirred at room temperature for 24h. After the reaction is completed, the reaction mixture is filtered through diatomaceous earth, rinsed with ethyl acetate, the organic phases are combined, and the solvent is removed by a rotary evaporator to obtain a crude product, which is separated by silica gel column chromatography, using petroleum ether and ethyl acetate as eluents, and finally obtaining a compound of formula 10 (isolation yield 72%).

[0075]

[0076] 1 H NMR (400 MHz, CDCl 3 )δ7.46 (d, J=7.6Hz, 2H), 7.37 (t, J=7.6Hz, 2H), 7.32-7.25 (m, 2H), 7.19 (d, J=6 .2Hz, 2H), 7.10 (d, J=7.4Hz, 2H), 6.65 (s, 1H), 3.49-3.32 (m, 2H), 2.36 (s, 3H); 13 C NMR (101 MHz, CDCl 3 )δδ208.8, 138.5, 134.6, 132.8, 128.72, 128.68, 128.6, 127.9, 127.6, 126.0, 12 5.9 (q, J=277.5Hz), 124.3, 100.1 (q, J=3.0Hz), 98.6, 35.3 (q, J=29.7Hz), 21.3; 19 F NMR (376 MHz, CDCl 3 )δ-64.5.

[0077] Embodiment 11

[0078] In a reaction tube with a stirrer, under N2 atmosphere, catalyst Cu(OTf)2 (0.02mmol, 10mol%), ligand α,α,α-terpyridine (0.04mmol, 20mol%), styrene (0.2mmol, 1equiv), p-methoxyphenylacetylene (0.3mmol, 1.5equiv), TongniII trifluoromethyl reagent (0.2mmol, 1equiv), potassium carbonate (0.6mmol, 3equiv), methanol solvent (0.7mL), acetonitrile solvent (0.3mL) were added in sequence, and stirred at room temperature for 24h. After the reaction was completed, the reaction mixture was filtered with diatomaceous earth, rinsed with ethyl acetate, the organic phases were combined, and the solvent was removed by rotary evaporator to obtain a crude product, which was separated by silica gel column chromatography, using petroleum ether and ethyl acetate as eluents, and finally the compound of formula 11 (isolation yield 62%) was obtained.

[0079]

[0080] 1 H NMR (400 MHz, CDCl 3 )δ7.44 (d, J=7.7Hz, 2H), 7.35 (t, J=7.5Hz, 2H), 7.31-7.26 (m, 3H), 6.89 (d, J=8.3Hz, 2H), 6.63 (s, 1H), 3.82 (s, 3H), 3.45-3.31 (m, 2H); 13 C NMR (101 MHz, CDCl 3 )δ208.3, 159.3, 134.8, 128.7, 128.4, 127.5, 126.0, 125.9 (q, J=277.5Hz), 125.1, 114.3, 100.1 (q, J=3.2Hz), 98.1, 55.3, 35.4 (q, J=29.6Hz); 19 F NMR (376 MHz, CDCl 3 )δ-64.5.

[0081] Example 12

[0082] In a reaction tube with a stirrer, N 2 Under the atmosphere, catalyst Cu(OTf) was added successively 2(0.02mmol, 10mol%), ligand α,α,α-terpyridine (0.04mmol, 20mol%), styrene (0.2mmol, 1equiv), p-trifluoromethylphenylacetylene (0.3mmol, 1.5equiv), TongniII trifluoromethyl reagent (0.2mmol, 1equiv), potassium carbonate (0.6mmol, 3equiv), methanol solvent (0.7mL), acetonitrile solvent (0.3mL), stirred at room temperature for 24h. After the reaction is completed, the reaction mixture is filtered through diatomaceous earth, rinsed with ethyl acetate, the organic phases are combined, and the solvent is removed by a rotary evaporator to obtain a crude product, which is separated by silica gel column chromatography, using petroleum ether and ethyl acetate as eluents, and finally obtaining a compound of formula 12 (isolation yield 73%).

[0083]

[0084] 1 H NMR (600 MHz, CDCl 3 )δ7.59 (d, J=8.1Hz, 2H), 7.46 (d, J=8.1Hz, 2H), 7.42 (d, J=.7.7Hz, 2H), 7. 37 (t, J=7.7Hz, 2H), 7.30 (t, J=7.3Hz, 1H), 6.69 (s, 1H), 3.47-3.32 (m, 2H); 13 CNMR (151MHz, CDCl 3 )δ209.3, 136.9, 133.8, 129.6 (q, J=32.9Hz), 128.8, 128.0, 127.3, 126.0, 125.8 (q, J=3.5Hz) , 125.7 (d, J=277.4Hz), 124.1 (d, J=271.9Hz), 101.1 (q, J=3.1Hz), 97.8, 35.2 (q, J=29.9Hz); 19 F NMR (565 MHz, CDCl 3 )δ-62.6, -64.6.

[0085] Embodiment 13

[0086] In a reaction tube with a stirrer, N 2Under atmosphere, catalyst Cu(OTf)2 (0.02mmol, 10mol%), ligand α,α,α-terpyridine (0.04mmol, 20mol%), styrene (0.2mmol, 1equiv), p-fluorophenylacetylene (0.3mmol, 1.5equiv), TongniII trifluoromethyl reagent (0.2mmol, 1equiv), potassium carbonate (0.6mmol, 3equiv), methanol solvent (0.7mL), acetonitrile solvent (0.3mL) were added in sequence, and stirred at room temperature for 24h. After the reaction was completed, the reaction mixture was filtered with diatomaceous earth, rinsed with ethyl acetate, the organic phases were combined, and the solvent was removed by rotary evaporator to obtain a crude product, which was separated by silica gel column chromatography, using petroleum ether and ethyl acetate as eluents, and finally the compound of formula 13 (isolation yield 76%) was obtained.

[0087]

[0088] 1 H NMR (400 MHz, CDCl 3 )δ7.44 (d, J=7.7Hz, 2H), 7.40-7.26 (m, 5H), 7.04 (t, J=8.6Hz, 2H), 3.49-3.27 (m, 2H); 13 C NMR (101 MHz, CDCl 3 )δ208.4 (d, J=2.3Hz), 162.4 (d, J=247.3Hz), 134.4, 128.9 (d, J=3.4Hz), 128.7, 128.6, 127.7, 1 26.0, 125.8 (q, J=277.5Hz), 115.8 (d, J=21.9Hz), 100.5 (q, J=3.1Hz), 97.7, 35.3 (q, J=29.7Hz); 19 F NMR (377 MHz, CDCl 3 )δ-64.5, -114.0.

[0089] Embodiment 14

[0090] In a reaction tube with a stirrer, under N2 atmosphere, the catalyst Cu(OTf) was added in sequence. 2(0.02mmol, 10mol%), ligand α, α, α-terpyridine (0.04mmol, 20mol%), styrene (0.2mmol, 1equiv), m-fluorophenylacetylene (0.3mmol, 1.5equiv), TongniII trifluoromethyl reagent (0.2mmol, 1equiv), potassium carbonate (0.6mmol, 3equiv), methanol solvent (0.7mL), acetonitrile solvent (0.3mL), stirred at room temperature for 24h. After the reaction is completed, the reaction mixture is filtered through diatomaceous earth, rinsed with ethyl acetate, the organic phases are combined, and the solvent is removed by a rotary evaporator to obtain a crude product, which is separated by silica gel column chromatography, using petroleum ether and ethyl acetate as eluents, and finally obtaining a compound of formula 14 (isolation yield 64%).

[0091]

[0092] 1 H NMR (400 MHz, CDCl 3 )δ7.46-7.42(m, 2H), 7.39-7.36(m, 2H), 7.33-7.28(m, 2H), 7.14(d, J=7.7Hz, 1H) , 7.07 (dt, J=9.9, 2.0Hz, 1H), 6.99-6.93 (m, 1H), 6.64 (s, 1H), 3.46-3.33 (m, 2H); 13 C NMR (101 MHz, CDCl 3 )δ208.8, 163.2 (d, J = 245.7Hz), 135.4 (d, J = 7.6Hz), 134.1, 130.2 (d, J = 8.5Hz), 128.8, 127.9, 126.0, 125.8 (q, J = 277.5Hz) , 122.9 (d, J = 2.7Hz), 114.6 (d, J = 21.3Hz), 113.7 (d, J = 22.3Hz), 100.8 (q, J = 3.1Hz), 98.0 (d, J = 2.5Hz), 35.3 (q, J = 29.8Hz); 19 F NMR (377 MHz, CDCl 3 )δ-64.5, -113.0.

[0093] Embodiment 15

[0094] In a reaction tube with a stirrer, N 2 Under the atmosphere, catalyst Cu(OTf) was added successively 2(0.02mmol, 10mol%), ligand α, α, α-terpyridine (0.04mmol, 20mol%), styrene (0.2mmol, 1equiv), p-chlorophenylacetylene (0.3mmol, 1.5equiv), TongniII trifluoromethyl reagent (0.2mmol, 1equiv), potassium carbonate (0.6mmol, 3equiv), methanol solvent (0.7mL), acetonitrile solvent (0.3mL), stirred at room temperature for 24h. After the reaction is completed, the reaction mixture is filtered through diatomaceous earth, rinsed with ethyl acetate, the organic phases are combined, and the solvent is removed by a rotary evaporator to obtain a crude product, which is separated by silica gel column chromatography, using petroleum ether and ethyl acetate as eluents, and finally obtaining a compound of formula 15 (isolation yield 70%).

[0095]

[0096] 1 H NMR (400 MHz, CDCl 3 )δ7.43 (d, J=7.8Hz, 2H), 7.37 (t, J=7.5Hz, 2H), 7.32-7.28 (m, 5H), 6.63 (s, 1H), 3.45-3.32 (m, 2H); 13 C NMR (101 MHz, CDCl 3 )δ208.7, 134.2, 133.4, 131.5, 129.0, 128.8, 128.3, 127.8, 126.0, 125.8 (q, J=277.5Hz), 100.7 (q, J=3.1Hz), 97.8, 35.3 (q, J=29.8Hz); 19 F NMR (377 MHz, CDCl 3 )δ-64.5.

[0097] Example 16

[0098] In a reaction tube with a stirrer, N 2 Under the atmosphere, catalyst Cu(OTf) was added successively 2(0.02mmol, 10mol%), ligand α, α, α-terpyridine (0.04mmol, 20mol%), styrene (0.2mmol, 1equiv), p-bromophenylacetylene (0.3mmol, 1.5equiv), TongniII trifluoromethyl reagent (0.2mmol, 1equiv), potassium carbonate (0.6mmol, 3equiv), methanol solvent (0.7mL), acetonitrile solvent (0.3mL), stirred at room temperature for 24h. After the reaction is completed, the reaction mixture is filtered through diatomaceous earth, rinsed with ethyl acetate, the organic phases are combined, and the solvent is removed by a rotary evaporator to obtain a crude product, which is separated by silica gel column chromatography, using petroleum ether and ethyl acetate as eluents, and finally obtaining a compound of formula 16 (isolation yield 70%).

[0099]

[0100] 1 H NMR (400 MHz, CDCl 3 )δ7.49-7.40(m, 4H), 7.38-7.35(m, 2H), 7.31-7.26(m, 1H), 7.23(d, J=8.5Hz, 2H), 6.61(s, 1H), 3.48-3.29(m, 2H); 13 C NMR (101 MHz, CDCl 3 )δ208.7, 134.1, 132.0, 128.8, 128.6, 127.8, 126.0, 125.8 (q, J=277.5Hz), 121.5, 100.8, 97.9, 35.2 (q, J=29.7Hz); 19 F NMR (377 MHz, CDCl 3 )δ-64.5.

[0101] Embodiment 17

[0102] In a reaction tube with a stirrer, under N2 atmosphere, catalyst Cu(OTf)2 (0.02mmol, 10mol%), ligand α, α, α-terpyridine (0.04mmol, 20mol%), styrene (0.2mmol, 1equiv), 2-ethynylpyridine (0.3mmol, 1.5equiv), TongniII trifluoromethyl reagent (0.2mmol, 1equiv), potassium carbonate (0.6mmol, 3equiv), methanol solvent (0.7mL), acetonitrile solvent (0.3mL) were added in sequence, and stirred at room temperature for 24h. After the reaction was completed, the reaction mixture was filtered with diatomaceous earth, rinsed with ethyl acetate, the organic phases were combined, and the solvent was removed by rotary evaporator to obtain a crude product, which was separated by silica gel column chromatography, using petroleum ether and ethyl acetate as eluents, and finally the compound of formula 17 (isolation yield 63%) was obtained.

[0103]

[0104] 1 H NMR (400 MHz, CDCl 3 )δ8.58 (d, J=4.8Hz, 1H), 7.62 (td, J=7.7, 1.7Hz, 1H), 7.48-7.43 (m, 3H), 7.36 (t, J =7.6Hz, 2H), 7.31-7.25(m, 1H), 7.18-7.07(m, 1H), 6.85(s, 1H), 3.51-3.31(m, 2H); 13 C NMR (101 MHz, CDCl 3 )δ210.2, 153.3, 149.7, 136.5, 133.8, 128.8, 127.9, 126.1, 125.7 (q, J=277.5Hz), 122.1, 121.8, 100.8 (q, J=3.1Hz), 100.3, 35.2 (q, J=30.0Hz); 19 FNMR (377 MHz, CDCl 3 )δ-64.5.

[0105] Embodiment 18

[0106] In a reaction tube with a stirrer, N 2 Under the atmosphere, catalyst Cu(OTf) was added successively 2(0.02mmol, 10mol%), ligand α,α,α-terpyridine (0.04mmol, 20mol%), styrene (0.2mmol, 1equiv), 2-ethynylthiophene (0.3mmol, 1.5equiv), TongniII trifluoromethyl reagent (0.2mmol, 1equiv), potassium carbonate (0.6mmol, 3equiv), methanol solvent (0.7mL), acetonitrile solvent (0.3mL), stirred at room temperature for 24h. After the reaction is completed, the reaction mixture is filtered through diatomaceous earth, rinsed with ethyl acetate, the organic phases are combined, and the solvent is removed by a rotary evaporator to obtain a crude product, which is separated by silica gel column chromatography, using petroleum ether and ethyl acetate as eluents, and finally obtaining a compound of formula 18 (isolation yield 79%).

[0107]

[0108] 1 H NMR (400 MHz, CDCl 3 )δ7.44 (d, J=7.7Hz, 2H), 7.36 (t, J=7.6Hz, 2H), 7.32-7.27 (m, 2H), 7.22 (d, J=2.6Hz, 1H), 7.13 (d, J=5.0Hz, 1H), 6.74 (s, 1H), 3.48-3.27 (m, 2H); 13 CNMR (101MHz, CDCl 3 ) δ208.9, 134.6, 134.0, 128.7, 127.6, 126.3, 126.1, 125.9 (q, J=277.5Hz), 122.2, 99.4 (q, J=3.2Hz), 93.0, 35.4 (q, J=29.6Hz); 19 F NMR (377 MHz, CDCl 3 )δ-64.5.

[0109] Embodiment 19

[0110] In a reaction tube with a stirrer, N 2 Under the atmosphere, catalyst Cu(OTf) was added successively 2(0.02mmol, 10mol%), ligand α,α,α-terpyridine (0.04mmol, 20mol%), styrene (0.2mmol, 1equiv), phenylacetylene (0.3mmol, 1.5equiv), TongniII trifluoromethyl reagent (0.2mmol, 1equiv), potassium carbonate (0.6mmol, 3equiv), methanol solvent (0.7mL), acetonitrile solvent (0.3mL), stirred at room temperature for 24h. After the reaction is completed, the reaction mixture is filtered through diatomaceous earth, rinsed with ethyl acetate, the organic phases are combined, and the solvent is removed by rotary evaporator to obtain a crude product, which is separated by silica gel column chromatography, using petroleum ether and ethyl acetate as eluents, and finally obtaining a compound of formula 19 (isolation yield 73%).

[0111]

[0112] 1 H NMR (400 MHz, CDCl 3 )δ7.48-7.44(m, 2H), 7.40-7.33(m, 6H), 7.30-7.27(m, 2H), 6.67(s, 1H), 3.50-3.30(m, 2H); 13 C NMR (101 MHz, CDCl 3 )δ208.7, 134.5, 132.9, 128.8, 128.7, 127.7, 127.6, 127.2, 126.0, 125.9 (q, J=277.5Hz), 100.3 (q, J=3.0Hz), 98.6, 35.3 (q, J=29.7Hz); 19 F NMR (376 MHz, CDCl 3 )δ-64.5.

[0113] Embodiment 20

[0114] In a reaction tube with a stirrer, N 2 Under the atmosphere, catalyst Cu(OTf) was added successively 2(0.02mmol, 10mol%), ligand α, α, α-terpyridine (0.04mmol, 20mol%), styrene (0.2mmol, 1equiv), 6-ethynylquinoline (0.3mmol, 1.5equiv), TongniII trifluoromethyl reagent (0.2mmol, 1equiv), potassium carbonate (0.6mmol, 3equiv), methanol solvent (0.7mL), acetonitrile solvent (0.3mL), stirred at room temperature for 24h. After the reaction is completed, the reaction mixture is filtered through diatomaceous earth, rinsed with ethyl acetate, the organic phases are combined, and the solvent is removed by a rotary evaporator to obtain a crude product, which is separated by silica gel column chromatography, using petroleum ether and ethyl acetate as eluents, and finally obtaining a compound of formula 20 (isolation yield 61%).

[0115]

[0116] 1 H NMR (400 MHz, CDCl 3 )δ7.44 (d, J=7.7Hz, 2H), 7.36 (t, J=7.6Hz, 2H), 7.32-7.27 (m, 2H), 7.22 (d, J=2.6Hz, 1H), 7.13 (d, J=5.0Hz, 1H), 6.74 (s, 1H), 3.48-3.27 (m, 2H); 13 CNMR (101MHz, CDCl 3 )δ208.9, 134.6, 134.0, 128.7, 127.6, 126.3, 126.1, 125.9 (q, J=277.5Hz), 122.2, 99.4 (q, J=3.2Hz), 93.0, 35.4 (q, J=29.6Hz); 19 F NMR (377 MHz, CDCl 3 )δ-64.5.

[0117] Example 21 Synthesis of target product with different ligands

[0118] In a reaction tube with a stirrer, N 2 Under the atmosphere, catalyst Cu(OTf) was added successively 2(0.02mmol, 10mol%), ligand (0.04mmol, 20mol%), styrene (0.2mmol, 1equiv), phenylacetylene (0.3mmol, 1.5equiv), TongniII trifluoromethyl reagent (0.2mmol, 1equiv), potassium carbonate (0.6mmol, 3equiv), methanol solvent (0.7mL), acetonitrile solvent (0.3mL), stirred at room temperature for 24h. The reaction results are shown in Table 1

[0119] Table 1 Synthesis results of different ligands

[0120]

[0121]

[0122] Example 22 Synthesis of target product from different copper salts

[0123] In a reaction tube with a stirrer, N 2 Under atmosphere, catalyst copper salt (0.02mmol, 10mol%), ligand (0.04mmol, 20mol%), styrene (0.2mmol, 1equiv), phenylacetylene (0.3mmol, 1.5equiv), TongniII trifluoromethyl reagent (0.2mmol, 1equiv), potassium carbonate (0.6mmol, 3equiv), methanol solvent (0.7mL), acetonitrile solvent (0.3mL) were added in sequence, and stirred at room temperature for 24h. The reaction results are shown in Table 2.

[0124] Table 2 Synthesis results of different copper salts

[0125] Copper salt The NMR yield of the compound of formula 19 Cu(OTf)2 78% (isolated yield 73%) Cu(OAc)2 53％ CuI 59％

[0126] Example 23 Synthesis of target product using different alkaline reagents

[0127] In a reaction tube with a stirrer, N 2 Under atmosphere, catalyst copper salt (0.02mmol, 10mol%), ligand (0.04mmol, 20mol%), styrene (0.2mmol, 1equiv), phenylacetylene (0.3mmol, 1.5equiv), TongniII trifluoromethyl reagent (0.2mmol, 1equiv), base (0.6mmol, 3equiv), methanol solvent (0.7mL), acetonitrile solvent (0.3mL) were added in sequence, and stirred at room temperature for 24h. The reaction results are shown in Table 3.

[0128] Table 3 Synthesis results of different alkaline reagents

[0129]

[0130]

[0131] Example 24 Synthesis of target product using different organic solvents

[0132] In a reaction tube with a stirrer, N 2 Under the atmosphere, catalyst copper salt (0.02mmol, 10mol%), ligand (0.04mmol, 20mol%), styrene (0.2mmol, 1equiv), phenylacetylene (0.3mmol, 1.5equiv), TongniII trifluoromethyl reagent (0.2mmol, 1equiv), base (0.6mmol, 3equiv), and 1mL of organic solvent were added in sequence, and stirred at room temperature for 24h. The reaction results are shown in Table 4.

[0133] Table 4 Synthesis results of different organic solvents

[0134] Organic solvents The NMR yield of the compound of formula 19 0.5mL acetonitrile + 0.5mL methanol 70％ 0.3mL acetonitrile + 0.7mL methanol 78% (isolated yield 73%)

[0135] Although the present invention has been described by the specific embodiments above, it should not be construed as being limited thereto; rather, the present invention encompasses the general aspects disclosed above. Various modifications and various embodiments are possible without departing from the spirit and scope of the present invention.

Claims

1. A method for synthesizing a copper-catalyzed trifluoromethyl allene compound, characterized in that: The method comprises the following steps: Dispersing an aromatic olefin compound, an aromatic alkyne compound, a Togni II trifluoromethyl reagent, a copper salt, a ligand, and an alkali reagent in an organic solvent, mixing them evenly to react, and obtaining a trifluoromethyl allene compound after the reaction is completed; The structural formula of the trifluoromethyl allene compound is: The structural formula of the Togni II trifluoromethyl reagent is: The structural formula of the aromatic olefin compound is: The structural formula of the aromatic alkyne compound is: Among them, Ar 1 ,Ar 2 is a substituted or unsubstituted aromatic ring, or a substituted or unsubstituted aromatic heterocycle; substitution includes mono- to tri-substitution, and the substituents are selected from: C1-8 alkyl, C1-8 alkoxy, halogen, and halogen-substituted C1-8 alkyl; The ligand includes any one or more of the following structures: R1 is selected from H, C1-4 alkyl; The copper salt is selected from any one or more of the following: Cu(OAc)2, CuI, and Cu(OTf)2; The alkaline reagent is any one or more of the following: K3PO4, Na2CO3, K2CO3 and Et3N; The organic solvent is methanol, or a mixed solvent of methanol and acetonitrile.

2. The method according to claim 1, characterized in that The synthetic route of the reaction is as follows:

3. The method for synthesizing a copper-catalyzed trifluoromethyl allene compound according to claim 1, characterized in that: Ar in the aromatic olefin structural formula 1 The group is any one of the following formulas 1 to 10:

4. The method for synthesizing a copper-catalyzed trifluoromethyl allene compound according to claim 1, characterized in that: Ar in the aromatic alkyne structural formula 2 The group is any one of the following formulas 11 to 22:

5. The method according to claim 1, characterized in that: The molar ratio of the aromatic olefin compound, the aromatic alkyne compound and the Togni II trifluoromethyl reagent is 1:1.5:1.

5.

6. The method according to claim 1, characterized in that The amount of the ligand used relative to the aromatic olefin compound is 20 mol%.

7. The method according to claim 1, characterized in that The amount of the copper salt used relative to the aromatic olefin compound is 10 mol%.

8. The method according to claim 1, characterized in that: The molar ratio of the alkaline reagent to the aromatic olefin compound is 3:1.

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