High Z / E selectivity heteroatom-trifluoromethylation reaction for photocatalysis of alkyne
By performing the high Z/E selective heteroatom-trifluoromethylation reaction of alkynes at room temperature by the visible light redox catalyst CF3SO2Na and the radical capture agent at room temperature, the problems of high cost of photocatalytic trifluoromethylation of alkynes and limited application scope of substrates in the prior art are solved, and the efficient and low-cost synthesis of alkynes compounds is achieved.
Patent Information
- Application Number
- CN202510759794.8
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-06-09
- Publication Date
- 2025-07-29
AI Technical Summary
In the existing alkyne photocatalytic trifluoromethylation reaction, there are problems such as high cost of metal catalysts and redox reagents, high toxicity, scarce fluorine-containing reagents and limited application scope of substrates.
The high Z/E selective heteroatom-trifluoromethylation reaction of alkynes is carried out at room temperature using the visible light redox catalyst CF3SO2Na and the free radical capture agent at room temperature, and the high selective synthesis of alkynes is achieved by blue light irradiation using low-cost photocatalysts such as 4CzIPN and free radical capture agents such as 1,3-dibromo-5,5-dimethylhydantoin.
The efficient, low-cost and green synthesis of alkyne compounds was achieved, and the highly selective Z/E products were obtained, which simplified the operation process and reduced the use of metal catalysts.
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Abstract
Description
Technical Field
[0001] The present invention relates to the technical field of trifluoromethyl compounds, and particularly to a photocatalytic highly Z / E selective heteroatom-trifluoromethylation reaction of alkynes. Background Art
[0002] Fluoroalkyl groups, especially trifluoromethyl groups, are crucial in improving the physical and biological properties of compounds, including metabolic stability, binding selectivity, bioavailability, and lipophilicity. Over the past few decades, various perfluoroalkylation methods have been developed rapidly. Trifluoromethylated alkenes are an important class of fluorinated drug molecules but do not occur naturally in nature. Examples include the anti-breast cancer drug panomifene, crop protectants such as cyhalothrin and its analog insecticides, and tetrapeptide prodrugs for the treatment of inflammatory diseases.
[0003]
[0004] In this regard, synthetic methods for the transition metal-catalyzed functionalized fluoroalkylated alkenes have been developed to achieve diverse modifications of triple bonds, including hydro-fluoroalkylation, halo-fluoroalkylation, carbon-fluoroalkylation, amino-fluoroalkylation, oxy-fluoroalkylation, and boryl-fluoroalkylation. Recently, photoredox catalysis has also been applied to trifluoromethylation reactions due to its environmental friendliness and versatility in synthetic reactions. However, the photocatalytic trifluoromethylation of alkynes mainly uses electrophilic trifluoromethyl sources through oxidative quenching, and then the vinyl radical is easily oxidized to a cationic form, making it vulnerable to nucleophilic attack. In addition, the alkenyl radical can also be trapped by hydrogen, halides, and π systems, thus forming trifluoromethylated products. Although significant progress has been made, there are still some drawbacks, such as the cost and toxicity of metal catalysts or redox reagents, the scarcity of sources of fluorinated reagents, the scope of substrates, and so on. Therefore, there is an urgent need to develop new and reliable methods for the synthesis of functionalized fluoroalkylated alkenes.
[0005] Herein, we describe a novel heteroatom-trifluoromethylation reaction of alkynes mediated by visible-light photoredox catalysis. CF3SO2Na is considered a convenient and easy-to-use nucleophilic trifluoromethyl reagent because they are inexpensive and stable in nature. In our method, this reagent is also found to be a key compound for achieving the difunctionalization of alkynes. The resulting vinyl radical intermediate can easily undergo bromo-trifluoromethylation, iodo-trifluoromethylation, thiol-trifluoromethylation, and seleno-trifluoromethylation reactions of alkynes with 1,3-dibromo-5,5-dimethylhydantoin, diiodomethane, disulfides, and diselenides. And by adjusting the reaction conditions, specific Z / E products can be obtained with high selectivity. Summary of the Invention
[0006] To solve the deficiencies of the existing technology, the purpose of the present invention is to provide a highly Z / E selective heteroatom-trifluoromethylation reaction of photocatalytic alkynes. This method uses alkynyl compounds, photocatalysts, radical scavengers, and CF3SO2Na as raw materials in a room temperature environment to achieve the highly Z / E selective synthesis of alkenyl compounds containing heteroatom-alkene-CF3.
[0007] To achieve the above purpose, the present invention adopts the following technical solutions:
[0008] A highly Z / E selective heteroatom-trifluoromethylation reaction of photocatalytic alkynes, comprising the following steps: using alkynes compounds, radical scavengers, and CF3SO2Na as raw materials, using a photocatalyst, irradiating the reaction under blue light at room temperature to obtain heteroatom-alkene-CF3.
[0009] Preferably, the alkynes compound has the following structure:
[0010]
[0011] Wherein, R is H, various substituted hydrocarbon groups, various substituted silyl groups; the hydrocarbon group is a straight-chain alkyl group, an alkyl group with a branched chain or an aryl group, or an aryl group.
[0012] Preferably, the radical scavenger is 1,3-dibromo-5,5-dimethylhydantoin, diiodomethane, disulfide, or diselenide.
[0013] Preferably, the photocatalyst is 4CzIPN, 3CzCIIPN, Ph-Mes-tBu-AcrBF4, Me-Mes-AcrClO4, fac-Ir(ppy)3, Ir(dF-CF3-ppy)2(dtbpy)PF6, or 3DPA2FBN.
[0014] Preferably, the photocatalyst is 3CzCIIPN.
[0015] Preferably, the blue light power is 24W, the wavelength is 450 - 465nm, and the irradiation reaction time is 8 - 24h.
[0016] Preferably, the solvent used in the reaction is DMSO.
[0017] Preferably, the structural formula of the heteroatom-alkene-CF3 is as follows:
[0018]
[0019] Preferably, in the heteroatom-alkene-CF3, E is Br, I, 2-chlorophenylthio, 2-thiophenylthio, 4-chlorophenylthio, benzylseleno, phenylseleno, or methylseleno.
[0020] Preferably, in the heteroatom-alkene-CF3, R is 1-phenyl-1-hydroxyethyl, 1-phenyl-1-hydroxymethylcyclopropyl, diphenylmethanol group, cyclohexanol group, N-methylphthalimide group, phenyl, methyl 4-methoxybenzoate group, 4-methoxy-N-benzamidomethyl, methyl isoxaconate group, methyl loxoprofen impurity 11 group, methyl 4-formylphenyl, 4-ethylbiphenyl.
[0021] Preferably, the heteroatom-alkene-CF3 is:
[0022]
[0023] and mixed, and mixed,
[0024]
[0025] Compared with the prior art, the present invention has the following beneficial effects:
[0026] The present invention provides an efficient synthesis method for heteroatom-alkene-CF3 products, using a new low-cost green photocatalytic route. The raw material alkyne compounds, radical scavengers and CF3SO2Na are widely sourced, simple to prepare, and have stable properties; the reaction operation is simple and the reaction is carried out at room temperature; an organic photocatalyst is used instead of a metal catalyst, which is highly efficient, green and has extremely low loading; the selectivity is high, and Z / E substrates can be obtained with high selectivity. BRIEF DESCRIPTION OF THE DRAWINGS
[0027] In order to more clearly illustrate the technical solutions of the embodiments of the present invention, the following will briefly introduce the drawings required in the embodiments. It should be understood that the following drawings only show some schematic diagrams of the embodiments of the present invention, and therefore should not be regarded as limiting the scope. For those of ordinary skill in the art, other related drawings can be obtained based on these drawings without creative efforts.
[0028] Figure 1 is the roadmap of the highly Z / E selective heteroatom-trifluoromethylation reaction of photocatalytic alkyne of the present invention;
[0029] Figure 2 is the 1H NMR spectrum of Preparation Example 13;
[0030] Figure 3 is the 13C NMR spectrum of Preparation Example 13;
[0031] Figure 4 is the 19F NMR spectrum of Preparation Example 13;
[0032] Figure 5 For preparing the hydrogen spectrum of Preparation Example 9;
[0033] Figure 6 For preparing the carbon spectrum of Preparation Example 9;
[0034] Figure 7 For preparing the fluorine spectrum of Preparation Example 9. Detailed implementation manners
[0035] In order to make the objectives, technical solutions and advantages of the present invention clearer, the present invention will be further described in detail below in conjunction with embodiments. Of course, the specific embodiments described herein are only used to explain the present invention and are not used to limit the present invention.
[0036] Unless otherwise specified, the chemical reagents and materials in the present invention are purchased through market channels or synthesized from raw materials purchased through market channels.
[0037] For a highly efficient synthesis method of a class of heteroatom-ethylene-CF3 alkenyl compounds provided by the present invention, please refer to the attached Figure 1 : Using an alkyne compound, a radical scavenger and CF3SO2Na as raw materials, DMSO as a solvent, using a low-loading photocatalyst, irradiating with blue light (24W) at room temperature for 8 - 24h, and after the reaction is completed, obtaining the target product by column chromatography separation means.
[0038] The present invention will be further described below through specific embodiments.
[0039] Preparation Example 1
[0040] Add 0.2 mmol of 2-phenyl-3-butyn-2-ol, 0.6 mmol of diiodomethane, 0.9 mmol of CF3SO2Na, 2 mL of DMSO, and 0.002 mmol of photocatalyst 3CzCIIPN into a 10 mL reaction tube, and irradiate with 450 nm blue light at room temperature for 12 h. After the reaction is completed, the heteroatom-alkene-CF3 product (E = I, R = 1-phenyl-1-hydroxyethyl) is obtained by column chromatography separation, with a yield of 84%, and only the Z configuration:
[0041]
[0042] Preparation Example 2
[0043] Add 0.2 mmol of 1-cyclopropyl-1-phenyl-2-propyn-1-ol, 0.6 mmol of diiodomethane, 0.9 mmol of CF3SO2Na, 2 mL of DMSO, and 0.002 mmol of the photocatalyst 3CzCIIPN into a 10 mL reaction tube. Irradiate with 450 nm blue light at room temperature for 12 h. After the reaction is completed, the heteroatom-olefin-CF3 product (E = I, R = 1-phenyl-1-hydroxy methyl cyclopropyl) is obtained by column chromatography separation, with a yield of 76%, and only the Z configuration:
[0044]
[0045] Preparation Example 3
[0046] Add 0.2 mmol of 1,1-diphenyl-2-propyn-1-ol, 0.6 mmol of diiodomethane, 0.9 mmol of CF3SO2Na, 2 mL of DMSO, and 0.002 mmol of the photocatalyst 3CzCIIPN into a 10 mL reaction tube. Irradiate with 450 nm blue light at room temperature for 12 h. After the reaction is completed, the heteroatom-olefin-CF3 product (E = I, R = diphenylmethanol group) is obtained by column chromatography separation, with a yield of 81%, and only the Z configuration:
[0047]
[0048] Preparation Example 4
[0049] Add 0.2 mmol of 1-ethynylcyclohexanol, 0.6 mmol of diiodomethane, 0.9 mmol of CF3SO2Na, 2 mL of DMSO, and 0.002 mmol of the photocatalyst 3CzCIIPN into a 10 mL reaction tube. Irradiate with 450 nm blue light at room temperature for 12 h. After the reaction is completed, the heteroatom-olefin-CF3 product (E = I, R = cyclohexanol group) is obtained by column chromatography separation, with a yield of 91%, and only the Z configuration:
[0050]
[0051] Preparation Example 5
[0052] Add 0.2 mmol of N-propargyl phthalimide, 0.6 mmol of diiodomethane, 0.9 mmol of CF3SO2Na, 2 mL of DMSO, and 0.002 mmol of the photocatalyst 3CzCIIPN into a 10 mL reaction tube. Irradiate with 450 nm blue light at room temperature for 12 h. After the reaction is completed, the heteroatom-olefin-CF3 product (E = I, R = N-methyl phthalimide group) is obtained by column chromatography separation, with a yield of 77%, and only the Z configuration:
[0053]
[0054] Preparation Example 6
[0055] In a 10 mL reaction tube, add 0.2 mmol of 3-phenyl-2-propyn-1-ol, 0.6 mmol of diiodomethane, 0.9 mmol of CF3SO2Na, 2 mL of DMSO, and 0.002 mmol of the photocatalyst 3CzCIIPN. Irradiate with 450 nm blue light at room temperature for 12 h. After the reaction, the heteroatom-olefin-CF3 product (E = I, R = phenyl) was obtained by column chromatography separation, with a yield of 75% and an E / Z configuration ratio of 3.2:1:
[0056]
[0057] Preparation Example 7
[0058] In a 10 mL reaction tube, add 0.2 mmol of 2-propyn-1-yl 4-methoxybenzoate, 0.6 mmol of diiodomethane, 0.9 mmol of CF3SO2Na, 2 mL of DMSO, and 0.002 mmol of the photocatalyst 3CzCIIPN. Irradiate with 450 nm blue light at room temperature for 12 h. After the reaction, the heteroatom-olefin-CF3 product (E = I, R = 4-methoxybenzoylmethyl) was obtained by column chromatography separation, with a yield of 86% and an E / Z configuration ratio of 3.1:1,
[0059]
[0060] Preparation Example 8
[0061] In a 10 mL reaction tube, add 0.2 mmol of 4-methoxy-N-(2-propyn-1-yl)benzamide, 0.6 mmol of diiodomethane, 0.9 mmol of CF3SO2Na, 2 mL of DMSO, and 0.002 mmol of the photocatalyst 3CzCIIPN. Irradiate with 450 nm blue light at room temperature for 12 h. After the reaction, the heteroatom-olefin-CF3 product (E = I, R = 4-methoxy-N-benzamidomethyl) was obtained by column chromatography separation, with a yield of 84% and an E / Z configuration ratio of 2.1:1,
[0062]
[0063] Preparation Example 9
[0064] Add 0.2 mmol of 2-(11-oxo-6,11-dihydrodibenzo[b,e]oxepin-9-yl)acetic acid 2-propyn-1-yl ester, 0.6 mmol of diiodomethane, 0.9 mmol of CF3SO2Na, 2 mL of DMSO, and 0.002 mmol of the photocatalyst 3CzCIIPN into a 10 mL reaction tube. Irradiate with 450 nm blue light at room temperature for 12 h. After the reaction is completed, the heteroatom-olefin-CF3 product (E = I, R = isoxazole methyl ester group) is obtained by column chromatography separation, with a yield of 71% and only the Z configuration:
[0065]
[0066] Preparation Example 10
[0067] Add 0.2 mmol of 2-(4-((2-oxocyclopentyl)methyl)phenyl)propanoic acid 2-propyn-1-yl ester, 0.6 mmol of diiodomethane, 0.9 mmol of CF3SO2Na, 2 mL of DMSO, and 0.002 mmol of the photocatalyst 3CzCIIPN into a 10 mL reaction tube. Irradiate with 450 nm blue light at room temperature for 12 h. After the reaction is completed, the heteroatom-olefin-CF3 product (E = I, R = loxoprofen impurity 11 methyl ester group) is obtained by column chromatography separation, with a yield of 65% and an E / Z configuration of 2.2:1:
[0068]
[0069] Preparation Example 11
[0070] Add 0.2 mmol of 4-ethylbiphenylacetylene, 0.6 mmol of 1,3-dibromo-5,5-dimethylhydantoin, 0.9 mmol of CF3SO2Na, 2 mL of DMSO, and 0.002 mmol of the photocatalyst 3CzCIIPN into a 10 mL reaction tube. Irradiate with 450 nm blue light at room temperature for 12 h. After the reaction is completed, the heteroatom-olefin-CF3 product (E = Br, R = 4-ethylbiphenyl) is obtained by column chromatography separation, with a yield of 53% and an E / Z configuration of 8.7:1:
[0071]
[0072] Preparation Example 12
[0073] Add 0.2 mmol of methyl 4-ethynylbenzoate, 0.6 mmol of 1,3-dibromo-5,5-dimethylhydantoin, 0.9 mmol of CF3SO2Na, 2 mL of DMSO, and 0.002 mmol of the photocatalyst 3CzCIIPN into a 10 mL reaction tube. Irradiate with 450 nm blue light at room temperature for 12 h. After the reaction is completed, the heteroatom-olefin-CF3 product (E = Br, R = 4-(methoxycarbonyl)phenyl) is obtained by column chromatography separation with a yield of 71%, and only the E configuration:
[0074]
[0075] Preparation Example 13
[0076] Add 0.2 mmol of methyl 4-ethynylbenzoate, 0.6 mmol of 1,2-bis(2-chlorophenyl) disulfide, 0.9 mmol of CF3SO2Na, 2 mL of DMSO, and 0.002 mmol of the photocatalyst 3CzCIIPN into a 10 mL reaction tube. Irradiate with 450 nm blue light at room temperature for 12 h. After the reaction is completed, the heteroatom-olefin-CF3 product (E = 2-chlorophenylthio, R = 4-(methoxycarbonyl)phenyl) is obtained by column chromatography separation with a yield of 61%, and only the Z configuration:
[0077]
[0078] Preparation Example 14
[0079] Add 0.2 mmol of methyl 4-ethynylbenzoate, 0.6 mmol of dithiophene disulfide, 0.9 mmol of CF3SO2Na, 2 mL of DMSO, and 0.002 mmol of the photocatalyst 3CzCIIPN into a 10 mL reaction tube. Irradiate with 450 nm blue light at room temperature for 12 h. After the reaction is completed, the heteroatom-olefin-CF3 product (E = 2-thienylthio, R = 4-(methoxycarbonyl)phenyl) is obtained by column chromatography separation with a yield of 55%, and only the Z configuration:
[0080]
[0081] Preparation Example 15
[0082] In a 10 mL reaction tube, add 0.2 mmol of methyl 4-ethynylbenzoate, 0.6 mmol of 1,2-bis(4-chlorophenyl) disulfide, 0.9 mmol of CF3SO2Na, 2 mL of DMSO, and 0.002 mmol of the photocatalyst 3CzCIIPN. Irradiate with 450 nm blue light at room temperature for 12 h. After the reaction is completed, the heteroatom-olefin-CF3 product (E = 4-chlorophenylthio, R = 4-(methoxycarbonyl)phenyl) is obtained by column chromatography separation, with a yield of 59%, and only the Z configuration:
[0083]
[0084] Preparation Example 16
[0085] In a 10 mL reaction tube, add 0.2 mmol of methyl 4-ethynylbenzoate, 0.6 mmol of dibenzyl diselenide, 0.9 mmol of CF3SO2Na, 2 mL of DMSO, and 0.002 mmol of the photocatalyst 3CzCIIPN. Irradiate with 450 nm blue light at room temperature for 12 h. After the reaction is completed, the heteroatom-olefin-CF3 product (E = benzylseleno, R = 4-(methoxycarbonyl)phenyl) is obtained by column chromatography separation, with a yield of 48%, and only the Z configuration:
[0086]
[0087] Preparation Example 17
[0088] In a 10 mL reaction tube, add 0.2 mmol of methyl 4-ethynylbenzoate, 0.6 mmol of diphenyl diselenide, 0.9 mmol of CF3SO2Na, 2 mL of DMSO, and 0.002 mmol of the photocatalyst 3CzCIIPN. Irradiate with 450 nm blue light at room temperature for 12 h. After the reaction is completed, the heteroatom-olefin-CF3 product (E = phenylseleno, R = 4-(methoxycarbonyl)phenyl) is obtained by column chromatography separation, with a yield of 65%, and only the Z configuration:
[0089]
[0090] Preparation Example 18
[0091] In a 10 mL reaction tube, add 0.2 mmol of methyl 4-ethynylbenzoate, 0.6 mmol of dimethyl diselenide, 0.9 mmol of CF3SO2Na, 2 mL of DMSO, and 0.002 mmol of the photocatalyst 3CzCIIPN. Irradiate with 450 nm blue light at room temperature for 12 h. After the reaction is completed, the heteroatom-olefin-CF3 product (E = methylseleno, R = 4-(methoxycarbonyl)phenyl) is obtained by column chromatography separation, with a yield of 36%, and only the Z configuration:
[0092]
[0093] As described above, it is only the preferred specific embodiment of the present invention, but the protection scope of the present invention is not limited thereto. Any person skilled in the art within the technical scope disclosed by the present invention, according to the technical solution and inventive concept of the present invention, making equivalent substitutions or changes, shall be covered by the protection scope of the present invention.
Claims
1. A highly Z / E selective heteroatom-trifluoromethylation reaction of photocatalytic alkynes, characterized in that, It includes the following steps: using an alkyne compound, a radical scavenger, and CF3SO2Na as raw materials, and using a photocatalyst to irradiate the reaction under blue light at room temperature to obtain heteroatom-alkene-CF3.
2. The heteroatom-trifluoromethylation reaction according to claim 1, characterized in that, The alkyne compound has the following structure: Among them, R is H, various substituted hydrocarbon groups, or various substituted silyl groups; the hydrocarbon group is a straight-chain alkyl group, a branched or aryl-substituted alkyl group, or an aryl group.
3. The heteroatom-trifluoromethylation reaction according to claim 1, wherein The radical scavenger is 1,3-dibromo-5,5-dimethylhydantoin, diiodomethane, disulfide, or diselenide.
4. The heteroatom-trifluoromethylation reaction according to claim 1, characterized in that, The photocatalyst is 4CzIPN, 3CzCIIPN, Ph-Mes-tBu-AcrBF4, Me-Mes-AcrClO4, fac-Ir(ppy)3, Ir(dF-CF3-ppy)2(dtbpy)PF6, or 3DPA2FBN.
5. The heteroatom-trifluoromethylation reaction according to claim 1, characterized in that, The power of the blue light is 24 W, and the wavelength is 450 - 465 nm. The irradiation reaction time is 8 - 24 h.
6. The heteroatom-trifluoromethylation reaction according to claim 1, wherein The solvent used in the reaction is DMSO.
7. The heteroatom-trifluoromethylation reaction according to claim 1, characterized in that, The structural formula of the heteroatom-alkene-CF3 is as follows:
8. The heteroatom-trifluoromethylation reaction according to claim 7, wherein, In the heteroatom-alkene-CF3, E is Br, I, 2-chlorophenylthio, 2-thienylthio, 4-chlorophenylthio, benzylseleno, phenylseleno, or methylseleno.
9. The heteroatom-trifluoromethylation reaction according to claim 7, wherein In the heteroatom-alkene-CF3, R is 1-phenyl-1-hydroxyethyl, 1-phenyl-1-hydroxymethylcyclopropyl, diphenylmethanol, cyclohexanol, N-methylphthalimide, phenyl, 4-methoxybenzoate, 4-methoxy-N-benzamidomethyl, methyl isoxazole-5-carboxylate, methyl loxoprofen impurity 11, 4-formylphenyl, or 4-ethylbiphenyl.
10. The heteroatom-trifluoromethylation reaction according to claim 7, wherein, The heteroatom-alkene-CF3 is: Mix Mix