A method for preparing trifluoromethyl-containing pyrazolone compounds under visible light induction

Abstract

The application discloses a method for preparing a trifluoromethyl-containing pyrazolone compound under visible light irradiation, which prepares the trifluoromethyl-containing pyrazolone compound through a free radical addition / cyclization cascade reaction. Under visible light irradiation, the reaction generates CF3 free radicals through an electron donor-acceptor (EDA) complex formed by Togni reagent II and an organic base, without an external photocatalyst. The method can convert various N-methyl acryl hydrazides into target products with good to excellent yield. The method is simple in operation, easy to scale up, and has high functional group tolerance, and provides a sustainable synthesis path for the synthesis of functional heterocyclic compounds.

Description

Technical Field

[0001] This application relates to a method for the visible light-induced preparation of compounds containing trifluoromethylpyrazolone compounds, belonging to the field of organic synthesis technology. Background Technology

[0002] Pyrazolone compounds are an important class of five-membered heterocyclic structures, attracting widespread attention in drug development due to their diverse medicinal properties. Among them, the 2-pyrazolin-5-one core serves as a key pharmacodynamic skeleton for many bioactive molecules, and its derivatives are frequently used as intermediates in the synthesis of functionalized pyrazolone compounds. The multifunctionality of this structure has driven continuous exploration of synthetic routes for the 2-pyrazolin-5-one skeleton over the past few decades. Traditional synthetic methods mainly rely on the Knorr condensation reaction between β-keto esters and substituted hydrazines (Eur. J. Org. Chem. 2013, 2013, 5879–5885; Beilstein J. Org. Chem. 2017, 13, 1950–1956). In addition, other strategies can also achieve the synthesis of such molecular skeletons, such as the palladium-catalyzed cyclocarbonylation of 1,2-diaza-1,3-butadiene (Org. Lett. 2001, 3, 3651–3653), the palladium-catalyzed carbonylation coupling of α-chloroketones with hydrazine (Tetrahedron Lett. 2016, 57 3363–3367), and the gold-catalyzed tandem reaction of N-propynylhydrazone (J. Org. Chem. 2015, 80 9307–9313). However, these methods still have significant limitations, such as the use of expensive noble metal catalysts, the need for high-temperature conditions, and limited substrate applicability. Therefore, developing efficient and universal strategies for the synthesis of 2-pyrazolin-5-ones remains an important challenge in current synthetic chemistry research.

[0003] Visible light-induced radical addition / cyclization cascades are of great significance in the synthesis of nitrogen-containing heterocycles due to their unique photocatalytic redox properties and excellent ability to generate diverse radical species. For example, Jintao Yu used 4CzIPN as a photocatalyst to achieve visible light-induced sulfonation / cyclization reactions between N'-arylene-N-acryloylhydrazide and sulfonyl chloride to synthesize functionalized pyrazolone compounds (Chem. Commun. 2025, 61 1196-1199).

[0004] Introducing trifluoromethyl groups into organic compounds can significantly enhance their lipophilicity and metabolic stability. This structural modification not only alters the electronic properties and three-dimensional conformation of the molecule, thereby improving the potency and selectivity of candidate drugs, but also significantly affects key physicochemical properties such as boiling point and solubility. Radical trifluoromethylation has become an important strategy for introducing CF3 groups due to its mild conditions and good compatibility with various functional groups. For example, Pan Changduo achieved the synthesis of trifluoromethylated pyrazolones using an organic molecular photocatalyst (J. Org. Chem. 2025, 90, 9457-9467). Therefore, developing photocatalytic strategies without added organic or metal catalysts using inexpensive trifluoromethylating reagents remains extremely important for constructing trifluoromethylated pyrazolone compounds. Summary of the Invention

[0005] The purpose of this invention is to provide a method for the visible light-induced preparation of trifluoromethylpyrazolone compounds. This method uses visible light induction without the need for an external photocatalyst. It utilizes the electron donor-acceptor (EDA) complex formed by N-methacryloylhydrazone and Togni reagent II to efficiently construct trifluoromethylpyrazolone derivatives under mild conditions, thereby solving the problems of dependence on noble metal catalysts and harsh reaction conditions in existing synthesis methods.

[0006] To achieve the above-mentioned technical objectives, the technical solution adopted by the present invention is as follows:

[0007] A method for the visible light-induced preparation of trifluoromethylpyrazolone compounds, wherein the compound of formula 1 reacts with Togni reagent II under visible light, organic base, and solvent conditions to obtain the compound of formula 3.

[0008] ;

[0009] Among them, R 1 The following are phenyl, 4-tolyl, 3-tolyl, 2-tolyl, 4-methoxyphenyl, 4-chlorophenyl, 4-bromophenyl, 4-trifluoromethylphenyl, 3-fluorophenyl, 2-fluorophenyl, 2-thienyl, 2-pyridyl, cyclohexyl, cyclopropyl, tert-butyl, and isopropyl;

[0010] R 2 It is phenyl, 4-tolyl, 4-methoxyphenyl, 4-cyanophenyl, 4-fluorophenyl, 4-bromophenyl, 3-tolyl, 3-chlorophenyl or benzyl.

[0011] Preferably, the organic base is 1,8-diazabicyclo[5.4.0]undec-7-ene, triethylenediamine, potassium carbonate, or potassium tert-butoxide.

[0012] Preferably, the organic solvent is acetonitrile, dimethyl sulfoxide, ethanol, methanol, tetrahydrofuran, or N,N-dimethylformamide.

[0013] Preferably, the wavelength of the visible light source is 420-430nm, 390-400nm, 380-390nm, or 380-780nm.

[0014] Preferably, the molar ratio of the compound of Formula 1 to Togni reagent II is 1:2.

[0015] Preferably, the molar ratio of the organic base to Togni reagent II is 1:1.

[0016] Compared with the prior art, the beneficial effects of the present invention are:

[0017] 1) It does not require expensive precious metal catalysts and organic photocatalysts. Under visible light induction, free radical trifluoromethylation / cyclization tandem reaction occurs to form electron donor-acceptor (EDA) complex, which is green and environmentally friendly and has significant economic benefits.

[0018] 2) The reaction conditions are mild, the applicability is wide, and the functional group compatibility is good;

[0019] 3) The method of this invention accurately and efficiently synthesizes trifluoromethylpyrazolone compounds, is simple to operate, and is easy to promote. Attached Figure Description

[0020] Figure 1 The proton spectrum of product 3a from Example 1 of this invention;

[0021] Figure 2 The carbon spectrum of product 3a from Example 1 of this invention;

[0022] Figure 3 The fluorine spectrum of product 3a from Example 1 of this invention;

[0023] Figure 4 The 3m proton spectrum of the product of Example 2 of this invention;

[0024] Figure 5 The carbon spectrum of product 3m in Example 2 of this invention;

[0025] Figure 6 The fluorine spectrum of product 3m in Example 2 of this invention;

[0026] Figure 7 The proton spectrum of product 3q in Example 3 of this invention;

[0027] Figure 8 The carbon spectrum of product 3q in Example 3 of this invention;

[0028] Figure 9The fluorine spectrum of product 3q in Example 3 of this invention;

[0029] Figure 10 The proton spectrum of product 3w from Example 4 of this invention;

[0030] Figure 11 The carbon spectrum of product 3w from Example 4 of this invention;

[0031] Figure 12 The fluorine spectrum of product 3w from Example 4 of this invention. Detailed Implementation

[0032] The technical solution of the present invention will be further described below with reference to specific embodiments, but it is not limited thereto.

[0033] Example 1

[0034] A method for the visible light-induced preparation of trifluoromethylpyrazolone compounds is illustrated in the flowchart below:

[0035]

[0036] The specific steps are as follows:

[0037] Under an argon atmosphere, the following substances were added to a Schlenk reaction tube equipped with a magnetic stirrer: N-methacryloylhydrazone (0.2 mmol), Togni reagent II (0.4 mmol), DABCO (0.4 mmol), and anhydrous acetonitrile (2.0 mL). The reaction mixture was then stirred continuously at room temperature and irradiated with a 390–400 nm LED light source for 12 hours. After the reaction was complete (monitored by TLC), 10 mL of water was added to dilute the mixture, and it was extracted three times with ethyl acetate (10 mL each time). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to remove the solvent. The crude product was purified by silica gel column chromatography using a gradient elution of petroleum ether / ethyl acetate (volume ratio from 10:1 to 4:1) to obtain trifluoromethyl-substituted pyrazolone product 3a, which was a colorless oily liquid in 91% yield.

[0038] Characterization results: 1 H NMR(400 MHz, CDCl3) δ 8.02-7.99 (m, 2H), 7.88-7.85 (m,2H), 7.48-7.43 (m, 5H), 7.27-7.22 (m, 1H), 3.07-2.89 (m, 2H), 1.65 (s, 3H); 13CNMR(101 MHz, CDCl3) δ 174.5, 159.0, 138.0, 130.69, 130.66, 129.07, 129.05,126.4, 125.8, 124.7 (q, J = 279.8 Hz), 119.4, 49.6 (q, J = 2.2 Hz), 40.8 (q, J =29.3 Hz), 23.9; 19 F NMR(376 MHz, CDCl3) δ -63.27;HRMS(ESI) m / z: [M + H] + Calcdfor C 18 H 16 F3N2O + 333.1209; found 333.1212. See Figures 1-3 As shown.

[0039] Example 2

[0040] A method for the visible light-induced preparation of trifluoromethylpyrazolone compounds is illustrated in the flowchart below:

[0041]

[0042] The specific steps are as follows:

[0043] Under an argon atmosphere, the following substances were added to a Schlenk reaction tube equipped with a magnetic stirrer: N-methacryloylhydrazone (0.2 mmol), Togni reagent II (0.4 mmol), DBU (0.4 mmol), and DMF (2.0 mL). The reaction mixture was then stirred continuously at room temperature and irradiated with a 390–400 nm LED light source for 12 hours. After the reaction was complete (monitored by TLC), 10 mL of water was added to dilute the mixture, and it was extracted three times with ethyl acetate (10 mL each time). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to remove the solvent. The crude product was purified by silica gel column chromatography using a gradient elution of petroleum ether / ethyl acetate (volume ratio from 10:1 to 4:1) to give 3m of trifluoromethyl-substituted pyrazolone product, which was an orange oily liquid with a yield of 67%.

[0044] Characterization results: 1H NMR(400 MHz, CDCl3) δ 7.98-7.96 (m, 2H), 7.49-7.42 (m,4H), 7.27-7.23 (m, 1H), 7.14 (dd, J = 5.1, 3.7 Hz, 1H), 3.07-2.85 (m, 2H), 1.64(s, 3H); 13 C NMR (101 MHz, CDCl3) δ 173.7, 155.3, 137.8, 134.0, 129.1, 128.6,127.9, 127.1, 126.0, 124.6 (q, J = 279.8 Hz), 119.4, 49.7 (q, J = 2.3 Hz), 40.7(q, J = 29.5 Hz), 24.0; 19 F NMR(376 MHz, CDCl3) δ -63.21;HRMS(ESI) m / z: [M + H] + Calcd for C 16 H 14 F3N2OS + 339.0773; found 339.0773. See Figures 4-6 .

[0045] Example 3

[0046] A method for the visible light-induced preparation of trifluoromethylpyrazolone compounds is illustrated in the flowchart below:

[0047]

[0048] The specific steps are as follows:

[0049] Under an argon atmosphere, the following substances were added to a Schlenk reaction tube equipped with a magnetic stirrer: N-methacryloylhydrazone (0.2 mmol), Togni reagent II (0.4 mmol), K₂CO₃ (0.4 mmol), and THF (2.0 mL). The reaction mixture was then stirred continuously at room temperature and irradiated with a 380–390 nm LED light source for 12 hours. After the reaction was complete (monitored by TLC), 10 mL of water was added to dilute the mixture, and it was extracted three times with ethyl acetate (10 mL each time). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to remove the solvent. The crude product was purified by silica gel column chromatography using a gradient elution of petroleum ether / ethyl acetate (volume ratio from 10:1 to 4:1) to give the trifluoromethyl-substituted pyrazolone product 3q, which was a colorless oily liquid in 71% yield.

[0050] Characterization results: 1 H NMR(400 MHz, CDCl3) δ 7.91-7.88 (m, 2H), 7.41-7.37 (m,2H), 7.21-7.16 (m, 1H), 2.82-2.74 (m, 2H), 1.49 (s, 3H), 1.38 (s, 9H); 13 C NMR (101 MHz, CDCl3) δ 173.8, 169.6, 138.1, 128.9, 125.3, 124.7 (q, J = 278.8 Hz), 119.1, 50.1 (q, J = 2.3 Hz), 40.8 (q, J = 28.8 Hz), 36.8, 29.8, 22.6; 19 F NMR(376MHz, CDCl3) δ -63.05;HRMS(ESI) m / z: [M + H] + Calcd for C 16 H 20 F3N2O + 313.1522; found 313.1526. See Figures 7-9 .

[0051] Example 4

[0052] A method for the visible light-induced preparation of trifluoromethylpyrazolone compounds is illustrated in the flowchart below:

[0053]

[0054] The specific steps are as follows:

[0055] Under an argon atmosphere, the following substances were added to a Schlenk reaction tube equipped with a magnetic stirrer: N-methacryloylhydrazone (0.2 mmol), Togni reagent II (0.4 mmol), potassium tert-butoxide (0.4 mmol), and anhydrous methanol (2.0 mL). The reaction mixture was then stirred continuously at room temperature and irradiated with a 420-430 nm LED light source for 12 hours. After the reaction was complete (monitored by TLC), 10 mL of water was added to dilute the mixture, and it was extracted three times with ethyl acetate (10 mL each time). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to remove the solvent. The crude product was purified by silica gel column chromatography using a gradient elution of petroleum ether / ethyl acetate (volume ratio from 10:1 to 4:1) to give 3w of trifluoromethyl-substituted pyrazolone product, which was an orange oily liquid in 81% yield.

[0056] Characterization results: 1 H NMR(400 MHz, CDCl3) δ 7.98-7.94 (m, 2H), 7.86-7.83 (m,2H), 7.48-7.46 (m, 3H), 7.15-7.10 (m, 3H), 3.08-2.87 (m, 2H), 1.65 (s, 3H); 13 CNMR(101 MHz, CDCl3) δ 174.3, 160.4 (d, J = 246.4 Hz), 159.2, 134.1 (d, J = 2.9Hz), 130.8, 130.5, 129.1, 126.4, 124.7 (q, J = 278.8 Hz), 121.2 (d, J = 8.1 Hz), 115.8 (d, J = 22.6 Hz), 49.6 (q, J = 2.2 Hz), 40.8 (q, J = 29.3 Hz), 23.9; 19 F NMR(376 MHz, CDCl3) δ -63.31, -116.21;HRMS(ESI) m / z: [M+H] + Calcd for C 18 H 15 F4N2O +351.1115; found 351.1118. See Figures 10-12 .

[0057] The present invention uses the above method to prepare a series of compounds containing trifluoromethylpyrazolones. The specific product structures and yields of the compounds are shown below.

[0058]

[0059] The above-mentioned products were successfully prepared using the method of the present invention, which solves the problems of dependence on noble metal catalysts and harsh reaction conditions in existing synthesis methods.

[0060] Comparative Example 1

[0061] A method for the visible light-induced preparation of trifluoromethylpyrazolone compounds is illustrated in the flowchart below:

[0062]

[0063] The specific steps are as follows:

[0064] Under an argon atmosphere, the following substances were added to a Schlenk reaction tube equipped with a magnetic stirrer: N-methacryloylhydrazone (0.2 mmol), Togni reagent II (0.4 mmol), and anhydrous acetonitrile (2.0 mL). The reaction mixture was then stirred continuously at room temperature and irradiated with a 390–400 nm LED light source for 12 hours. After the reaction was complete (monitored by TLC), 10 mL of water was added to dilute the mixture, and it was extracted three times with ethyl acetate (10 mL each time). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to remove the solvent. The crude product was purified by silica gel column chromatography using a gradient elution of petroleum ether / ethyl acetate (volume ratio from 10:1 to 4:1), yielding only trace amounts of the trifluoromethyl-substituted pyrazolone product 3a in extremely low yield.

[0065] Comparative Example 2

[0066] A method for the visible light-induced preparation of trifluoromethylpyrazolone compounds is illustrated in the flowchart below:

[0067]

[0068] The specific steps are as follows:

[0069] Under an argon atmosphere, the following substances were added to a Schlenk reaction tube equipped with a magnetic stirrer: N-methacryloylhydrazone (0.2 mmol), Togni reagent II (0.4 mmol), DABCO (0.4 mmol), and anhydrous acetonitrile (2.0 mL). The reaction mixture was then stirred continuously at room temperature and reacted in the dark for 12 hours. After the reaction was completed, the trifluoromethyl-substituted pyrazolone product 3a was not obtained by analysis.

[0070] Comparative Example 3

[0071] A method for the visible light-induced preparation of trifluoromethylpyrazolone compounds is illustrated in the flowchart below:

[0072]

[0073] The specific steps are as follows:

[0074] Under air atmosphere, the following substances were added to a Schlenk reaction tube equipped with a magnetic stirrer: N-methacryloylhydrazone (0.2 mmol), Togni reagent II (0.4 mmol), DABCO (0.4 mmol), and anhydrous acetonitrile (2.0 mL). The reaction mixture was then stirred continuously at room temperature and irradiated with a 390–400 nm LED light source for 12 hours. After the reaction was completed (monitored by TLC), 10 mL of water was added to dilute the mixture, and it was extracted three times with ethyl acetate (10 mL each time). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to remove the solvent. The crude product was purified by silica gel column chromatography using a gradient elution of petroleum ether / ethyl acetate (volume ratio from 10:1 to 4:1) to obtain trifluoromethyl-substituted pyrazolone product 3a, which was a colorless oily liquid with a yield of only 18%.

[0075] It should be noted that the above embodiments are merely some preferred embodiments of the present invention, and not all embodiments. Obviously, based on the above embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort should fall within the scope of protection of the present invention.

Claims

1. A method for the visible light-induced preparation of compounds containing trifluoromethylpyrazolone derivatives, characterized in that, The compound of Formula 1 reacts with Togni reagent II under visible light, organic base, and solvent conditions to yield the compound of Formula 3. ； Among them, R 1 The following are phenyl, 4-tolyl, 3-tolyl, 2-tolyl, 4-methoxyphenyl, 4-chlorophenyl, 4-bromophenyl, 4-trifluoromethylphenyl, 3-fluorophenyl, 2-fluorophenyl, 2-thienyl, 2-pyridyl, cyclohexyl, cyclopropyl, tert-butyl, and isopropyl; R 2 It is phenyl, 4-tolyl, 4-methoxyphenyl, 4-cyanophenyl, 4-fluorophenyl, 4-bromophenyl, 3-tolyl, 3-chlorophenyl, or benzyl; The organic base is 1,8-diazabicyclo[5.4.0]undec-7-ene, triethylenediamine, potassium carbonate, or potassium tert-butoxide; The molar ratio of the organic base to Togni reagent II is 1:

1.

2. The method for preparing trifluoromethylpyrazolone compounds induced by visible light according to claim 1, characterized in that, The organic solvent is acetonitrile, dimethyl sulfoxide, ethanol, methanol, tetrahydrofuran, or N,N-dimethylformamide.

3. The method for preparing trifluoromethylpyrazolone compounds induced by visible light according to claim 1, characterized in that, The wavelength of the visible light source is 420-430nm, 390-400nm, 380-390nm or 380-780nm.

4. The method for preparing trifluoromethylpyrazolone compounds induced by visible light according to claim 1, characterized in that, The molar ratio of the compound of Formula 1 to Togni reagent II is 1:2.

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