Preparation method for direct trifluoromethylation of pyrimidinedione herbicides through visible light catalysis
The direct trifluoromethylation of pyrimidine dione herbicides using visible light photocatalysis solves the problems of herbicide resistance and residues in pyrimidine dione herbicides, simplifies the synthesis process, reduces costs, and improves the bioactivity and environmental safety of the drugs.
Patent Information
- Application Number
- CN202511322670.X
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-09-16
- Publication Date
- 2026-01-13
AI Technical Summary
Existing pyrimidine dione herbicides have problems with resistance and residues, and traditional synthesis methods are complex and costly.
Using visible light catalysis, a photocatalyst, a pyrimidine dione herbicide, a trifluoromethylating agent, copper acetate, and triethylamine are reacted under visible light to achieve trifluoromethylation through activation of the C-5 carbon-hydrogen bond.
It simplifies the synthesis process, reduces costs, improves the bioactivity and environmental safety of pyrimidine dione herbicides, and reduces the risk of herbicide resistance.
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Figure CN121318862A_ABST
Abstract
Description
Technical Field
[0001] This invention belongs to the technical fields of photocatalytic organic synthesis and pesticide herbicides, specifically to a method for the direct trifluoromethylation of pyrimidine dione herbicides under visible light catalysis. Background Technology
[0002] Protoporphyrinogen oxidase (PPO) inhibitor herbicides have become an important category in the field of non-selective weed control due to their high activity, broad spectrum of weed control, low residue, low risk of resistance, and low toxicity to mammals. Among them, pyrimidine dione herbicides are currently the most widely studied PPO inhibitors on the market. Representative commercial agents include sulfadiazine, flupyrazosulfuron, flupropargyl, and flupyrazosulfuron, which have advantages such as high selectivity, low cost, excellent efficacy, and ease of use (J. Agric. Food Chem. 2010, 58, 2643-2651).
[0003] However, long-term application of a single type of herbicide can easily lead to herbicide resistance in weeds, and some herbicides may remain in the soil, causing environmental pollution problems. Therefore, optimizing herbicide performance and reducing the risk of resistance through targeted structural modification has become a research hotspot in this field.
[0004] Photocatalytic organic synthesis technology has attracted widespread attention from academia and industry in recent years due to its simple operation, precise functionalization, and environmental friendliness. Nitrogen-containing heterocyclic compounds have unique biochemical properties, and their lipophilicity, biological activity, and antiviral properties can be effectively regulated through chemical functionalization (such as trifluoromethylation, alkylation, and acylation) (Org. Chem. Front., 2025, 12, 388; Proc. Natl. Acad. Sci. USA 108 (35)14411-14415). Among them, trifluoromethylation of nitrogen-containing heterocycles has become a research focus because the trifluoromethyl group (-CF3) can significantly improve the metabolic stability, lipophilicity, and biological activity of the molecule.
[0005] Based on this, the present invention realizes the direct trifluoromethylation of pyrimidine dione herbicides through photocatalysis, which can not only improve atom economy and reduce industrial waste, but also optimize the herbicidal activity and environmental safety of herbicides in a targeted manner, and has important theoretical and applied value. Summary of the Invention
[0006] The present invention aims to provide a method for the preparation of pyrimidine dione herbicides by direct trifluoromethylation under visible light catalysis, in order to solve the problems of herbicide resistance and residue in existing herbicides, while the synthesis process is simple and low in cost.
[0007] The method for preparing visible light-catalyzed pyrimidine dione herbicides by direct trifluoromethylation includes the following steps: S1. A photocatalyst, a pyrimidine dione herbicide, a trifluoromethylating agent, copper acetate, triethylamine, and dimethyl sulfoxide are mixed and subjected to a photocatalytic reaction under visible light. S2. After the reaction is complete, add a hydrophilic solvent and a lipophilic solvent for extraction, and collect the organic phase; S3. After concentration, the organic phase was purified by silica gel column chromatography to obtain 5-trifluoromethylpyrimidine dione products.
[0008] This invention proposes a method for the direct trifluoromethylation of pyrimidine dione herbicides under visible light catalysis: using pyrimidine dione herbicides and trifluoromethylating reagents as raw materials, a photocatalyst, copper acetate as a photocatalytic auxiliary, and triethylamine as an acid-binding agent to abstract protons, keeping the system alkaline, and carrying out a photocatalytic reaction under visible light irradiation, thereby activating the C-5 carbon-hydrogen bond of the pyrimidine dione herbicide to achieve trifluoromethylation.
[0009] In the preferred embodiment, the molar ratio of the pyrimidine dione herbicide, trifluoromethylating agent, copper acetate, triethylamine and photocatalyst in step S1 is 1:1~5:0.05~0.15:1~3:0.02~0.07.
[0010] In a preferred embodiment, the trifluoromethylating agent in step S1 is selected from trifluoromethanesulfonyl chloride or sodium trifluoromethanesulfinate.
[0011] In a preferred embodiment, the photocatalyst described in step S1 is selected from bis[2-(2,4-difluorophenyl)-5-trifluoromethylpyridine][2-2''-bi(4-tert-butylpyridine)]iridium(III) hexafluorophosphate, 2,4,5,6-tetra(9-carbazolyl)isophthalonitrile, Bengal rose red, methylene blue, 10-methyl-9-trimethylmethylacrylidine perchlorate, or 9-trimethyl-10-phenylacrylidine tetrafluoroborate.
[0012] In the preferred embodiment, the visible light source mentioned in step S1 is a Kessil lamp with a wavelength of 430~470nm and a power of 10~40W.
[0013] In the preferred embodiment, the duration of the photocatalytic reaction in step S1 is 8-12 h.
[0014] In the preferred embodiment, the photocatalytic reaction described in step S1 is carried out at 20~30 °C.
[0015] In a preferred embodiment, the hydrophilic solvent in step S2 is selected from a saturated sodium chloride solution, and the lipophilic solvent is selected from dichloromethane or ethyl acetate.
[0016] In the preferred embodiment, the organic phase described in step S3 is dried with anhydrous sodium sulfate before concentration.
[0017] In a preferred embodiment, the eluent in the silica gel column in step S3 is petroleum ether and ethyl acetate in a volume ratio of 5 to 6:1.
[0018] Compared with the prior art, the beneficial effects of the present invention are as follows: 1. This invention is the first to achieve direct trifluoromethylation of pyrimidine dione herbicides under visible light catalysis, filling a technological gap in this field.
[0019] 2. This invention uses visible light as an energy source, operates under mild conditions (room temperature), is easy to operate, and does not require high-temperature or high-pressure equipment.
[0020] 3. The raw materials of this invention are readily available, the amount of catalyst used is low, the equipment is simple, the cost is low, and it is easy to scale up production.
[0021] 4. This invention effectively improves the bioactivity and resistance of pyrimidine dione herbicides by C-5 position trifluoromethylation of pyrimidine dione herbicides, thereby reducing the risk of environmental residues. Attached Figure Description
[0022] Appendix Figure 1 The equation for the C-5 trifluoromethylation reaction of pyrimisulfuron is given.
[0023] Appendix Figure 2 The structural formula is 5-trifluoromethylbenzimidazole.
[0024] Appendix Figure 3 The structural formula is 5-trifluoromethylflumethazine.
[0025] Appendix Figure 4 The structural formula is 5-trifluoromethylfluprofen. Detailed Implementation
[0026] The technical solution of the present invention will be further described and illustrated below through examples. All raw materials used in the examples are commercially available or prepared using conventional methods.
[0027] Example 1 A method for preparing pyrimisulfuron-methyl via visible light catalysis and direct trifluoromethylation includes the following steps: S1. At 25 °C, a magnetic stir bar, 0.2 mmol of pyrimisulfonamide, 1.0 mmol of sodium trifluoromethyl sulfinate, 0.01 mmol of photocatalyst bis[2-(2,4-difluorophenyl)-5-trifluoromethylpyridine][2-2''-bi(4-tert-butylpyridine)]iridium(III) hexafluorophosphate, 0.2 mmol of copper acetate, 0.4 mmol of triethylamine, and 2 mL of dimethyl sulfoxide were added sequentially to a Schlenk reaction tube. The photocatalytic reaction was carried out under the illumination of a Kessil lamp with a wavelength of 430 nm and a power of 40 W. The reaction equation is as follows. Figure 1 As shown, the reaction lasted for 12 hours; S2. After the reaction is complete, add 10 mL of saturated sodium chloride solution and 15 mL of dichloromethane, shake and extract 3 times, combine the organic phases and dry with anhydrous sodium sulfate. S3. The organic phase was concentrated by rotary evaporation at a temperature of 45-50 °C and a vacuum of 0.01 MPa. After concentration, the solution was passed through a silica gel column (eluent: V). 石油醚 / V 乙酸乙酯 (5:1) Chromatographic purification yielded 5-trifluoromethylphenylsulfonamide, with the structural formula shown below. Figure 2 As shown.
[0028] 0.2 mmol of benzoylpyrimethanil is equivalent to 100 mg, and theoretically, it produces 114 mg of 5-trifluoromethylbenzoylpyrimethanil. In this example, the yield of 5-trifluoromethylbenzoylpyrimethanil is 45.6 mg, with a yield of 40%.
[0029] The 1H NMR spectrum of 5-trifluoromethylbenzimidazine was obtained by TLC (thin-layer chromatography) as shown below: 1 H NMR (400 MHz, Chloroform- d ) δ 8.05 (s, 1H), 3.69 – 3.59 (m, 1H), 3.43 (s, 3H), 3.40 (s, 3H), 2.82 (s, 3H), 1.21 (d, J = 8.3 Hz, 6H).
[0030] Example 2 A method for preparing flupyrimisulfuron-methyl via visible light catalysis and direct trifluoromethylation includes the following steps: S1. At 25 °C, a magnetic stir bar, 0.2 mmol of flupyribac-methyl, 1.0 mmol of sodium trifluoromethyl sulfinate, 0.01 mmol of photocatalyst bis[2-(2,4-difluorophenyl)-5-trifluoromethylpyridine][2-2''-bi(4-tert-butylpyridine)]iridium(III) hexafluorophosphate, 0.2 mmol of copper acetate, 0.4 mmol of triethylamine, and 2 mL of dimethyl sulfoxide were added sequentially to a Schlenk reaction tube. The photocatalytic reaction was carried out under the irradiation of a Kessil lamp with a wavelength of 430 nm and a power of 40 W for 12 h. S2. After the reaction is complete, add 10 mL of saturated sodium chloride solution and 15 mL of dichloromethane, shake and extract 3 times, combine the organic phases and dry with anhydrous sodium sulfate. S3. The organic phase was concentrated by rotary evaporation at a temperature of 45-50 °C and a vacuum of 0.01 MPa. After concentration, the solution was passed through a silica gel column (eluent: V). 石油醚 / V 乙酸乙酯 The mixture was purified by chromatography at a ratio of 6:1 to obtain 5-trifluoromethylflumethoxysulfuron, with the structural formula shown below. Figure 3 As shown.
[0031] 0.2 mmol of benzosulfuron is 100 mg, and theoretically, it produces 116 mg of 5-trifluoromethyl flusulfuron. In this example, the yield of 5-trifluoromethyl flusulfuron is 30 mg, with a yield of 26%.
[0032] The 1H NMR spectrum of 5-trifluoromethylflumethazine was obtained by TLC (thin-layer chromatography) as shown below: 1 H NMR (400 MHz, Chloroform- d ) 7.66 (s, 1H), 7.38 (s, 1H), 4.02 (q, J = 5.8 Hz, 1H), 3.64 (s, 3H), 3.40 (s, 3H), 3.39 – 3.33 (m, 2H), 2.59 (t, J = 6.0 Hz, 2H).
[0033] Example 3 A method for preparing flupropargyl by direct trifluoromethylation under visible light catalysis includes the following steps: S1. At 25 °C, a magnetic stir bar, 0.2 mmol of flupropargyl ester, 1.0 mmol of sodium trifluoromethyl sulfinate, 0.01 mmol of photocatalyst bis[2-(2,4-difluorophenyl)-5-trifluoromethylpyridine][2-2''-bi(4-tert-butylpyridine)]iridium(III) hexafluorophosphate, 0.2 mmol of copper acetate, 0.4 mmol of triethylamine, and 2 mL of dimethyl sulfoxide were added sequentially to a Schlenk reaction tube. The photocatalytic reaction was carried out under the irradiation of a Kessil lamp with a wavelength of 430 nm and a power of 40 W for 12 h. S2. After the reaction is complete, add 10 mL of saturated sodium chloride solution and 15 mL of dichloromethane, shake and extract 3 times, combine the organic phases and dry with anhydrous sodium sulfate. S3. The organic phase was concentrated by rotary evaporation at a temperature of 45-50 °C and a vacuum of 0.01 MPa. After concentration, the solution was passed through a silica gel column (eluent: V). 石油醚 / V 乙酸乙酯 The mixture was purified by chromatography at a ratio of 6:1 to obtain 5-trifluoromethylfluprochloraz, with the structural formula shown below. Figure 4 As shown.
[0034] 0.2 mmol of flupropargyl is equivalent to 100 mg, and theoretically, it can produce 114 mg of 5-trifluoromethylflupropargyl. In this example, the yield of 5-trifluoromethylflupropargyl is 30 mg, with a yield of 25%.
[0035] The 1H NMR spectrum of 5-trifluoromethylfluprofen was obtained by TLC (thin-layer chromatography) as shown below: 1 H NMR (400 MHz, Chloroform- d ) δ 8.12 (d, J = 2.3 Hz, 1H), 7.58 (d, J = 8.9 Hz, 1H), 7.42 (dd, J = 8.9, 2.3 Hz, 1H), 5.98 – 5.86 (m, 1H), 5.37 – 5.24 (m, 2H), 4.64(d, J = 4.9 Hz, 2H), 3.40 (s, 3H).
[0036] Comparative Example 1 A method for the preparation of bensulfuron-methyl catalytic direct trifluoromethylation is basically the same as that in Example 1, except that the wavelength of the visible light in step S1 is 365 mm.
[0037] TLC (thin-layer chromatography) analysis showed that no target product was formed.
[0038] Comparative Example 2 A method for the preparation of pyrimisulfuron-methyl via visible light catalysis and direct trifluoromethylation. It is basically the same as Example 1, except that copper acetate and triethylamine are not added in step S1.
[0039] Calculations show that the yield of 5-trifluoromethylbenzylsulfuron in this comparative example will be 10%.
[0040] As can be seen from the yields of Example 1 and Comparative Example 2, the yield decreased by 75% without the addition of photocatalytic aids and acid-coating agents.
[0041] In the visible-light-catalyzed trifluoromethylation reaction, copper acetate, a photocatalytic catalytic aid, participates as a redox mediator in the formation of the key active intermediate (trifluoromethyl radical, ·CF3): Under visible light irradiation, the photocatalyst absorbs light energy and is excited to the excited state (PC), which has a strong electron transfer capability and can transfer electrons to Cu. 2+ , making Cu 2+ Reduced to Cu + (Cu) 2+ +PC→Cu + + PC + ); the generated Cu + It is the key species for activating the trifluoromethyl source, and can convert the trifluoromethyl source into ·CF3 through single electron transfer. ·CF3 is the active intermediate that directly attacks the 5-position of the benzene ring of pyrimisulfuron, and its formation efficiency directly determines the yield of the target product. When copper acetate is removed, only the photocatalyst participates in the formation of the key active intermediate (trifluoromethyl radical, ·CF3) as a redox mediator. The formation pathway of ·CF3 is reduced, the concentration of the active intermediate decreases, making the reaction difficult to proceed efficiently and the yield decreases.
[0042] Triethylamine, as an organic base (acidifier), primarily maintains the alkaline environment of the reaction system, ensuring the stability of the photocatalytic cycle and active species. During trifluoromethylation, the activation of the trifluoromethyl source may be accompanied by the generation of acidic byproducts. These acids can combine with the redox mediator, leading to its deactivation and hindering the formation of ·CF3. Triethylamine can neutralize these acidic byproducts, preventing Cu from forming. + Triethylamine can be protonated or precipitated to maintain its catalytic activity. In addition, triethylamine may stabilize the excited state (PC) of the photocatalyst by forming weak interactions with the photocatalyst or substrate, thereby reducing energy loss caused by nonradiative transitions and improving photocatalytic efficiency.
[0043] When triethylamine is removed, the acidity of the system increases, and Cu +The catalyst is prone to deactivation, and the stability of the excited state of the photocatalyst decreases, further reducing the generation efficiency of ·CF3 and resulting in a significant decrease in yield.
[0044] Copper acetate promotes the formation of the key active intermediate ·CF3 through a redox cycle, while triethylamine maintains the stability of the active species by neutralizing acidic byproducts. Together, they ensure the efficient conduct of the photocatalytic trifluoromethylation reaction. Removal of these two substances disrupts the ·CF3 formation pathway and deactivates the active species, ultimately reducing the yield of 5-trifluoromethylpyrimisulfuron from 40% to 10%.
[0045] It should be understood that the above embodiments are for illustrative purposes only and are not intended to limit the scope of protection of the present invention. Furthermore, it should be understood that after reading the teachings of this invention, those skilled in the art can make various alterations or modifications to the invention, and these equivalent forms also fall within the scope defined by the appended claims.
Claims
1. A method for preparing a pyrimidine dione herbicide by direct trifluoromethylation under visible light catalysis, characterized in that, Includes the following steps: S1. A photocatalyst, a pyrimidine dione herbicide, a trifluoromethylating agent, copper acetate, triethylamine, and dimethyl sulfoxide are mixed and subjected to a photocatalytic reaction under visible light. S2. After the reaction is complete, add a hydrophilic solvent and a lipophilic solvent for extraction, and collect the organic phase; S3. After concentration, the organic phase was purified by silica gel column chromatography to obtain 5-trifluoromethylpyrimidine dione products.
2. The method for preparing pyrimidine dione herbicides by direct trifluoromethylation according to claim 1, characterized in that, The molar ratio of the pyrimidine dione herbicide, trifluoromethylating agent, copper acetate, triethylamine and photocatalyst mentioned in step S1 is 1:1~5:0.05~0.15:1~3:0.02~0.
07.
3. The method for preparing pyrimidine dione herbicides by direct trifluoromethylation under visible light catalysis according to claim 1, characterized in that, The trifluoromethylating agent mentioned in step S1 is selected from trifluoromethylsulfonyl chloride or sodium trifluoromethylsulfinate.
4. The method for preparing pyrimidine dione herbicides by direct trifluoromethylation according to claim 1, characterized in that, The photocatalyst described in step S1 is selected from bis[2-(2,4-difluorophenyl)-5-trifluoromethylpyridine][2-2''-bi(4-tert-butylpyridine)]iridium(III) hexafluorophosphate, 2,4,5,6-tetra(9-carbazolyl)isophthalonitrile, Bengal rose red, methylene blue, 10-methyl-9-trimethylmethylacrylidine perchlorate or 9-trimethyl-10-phenylacrylidine tetrafluoroborate.
5. The method for preparing pyrimidine dione herbicides by direct trifluoromethylation under visible light catalysis according to claim 1, characterized in that, The visible light source mentioned in step S1 is a Kessil lamp with a wavelength of 430~470 nm and a power of 10~40 W.
6. The method for preparing pyrimidine dione herbicides by direct trifluoromethylation under visible light catalysis according to claim 1, characterized in that, The duration of the photocatalytic reaction described in step S1 is 8-12 h.
7. The method for preparing pyrimidine dione herbicides by direct trifluoromethylation under visible light catalysis according to claim 1, characterized in that, The photocatalytic reaction described in step S1 is carried out at 20~30 °C.
8. The method for preparing pyrimidine dione herbicides by direct trifluoromethylation according to claim 1, characterized in that, The hydrophilic solvent mentioned in step S2 is selected from saturated sodium chloride solution, and the lipophilic solvent is selected from dichloromethane or ethyl acetate.
9. The method for preparing pyrimidine dione herbicides by direct trifluoromethylation according to claim 1, characterized in that, The organic phase described in step S3 is dried with anhydrous sodium sulfate before concentration.
10. The method for preparing pyrimidine dione herbicides by direct trifluoromethylation according to claim 1, characterized in that, The eluent in the silica gel column in step S3 is petroleum ether and ethyl acetate in a volume ratio of 5 to 6:1.