A method for preparing a beta-trifluoromethyl enamine compound based on organic dye catalysis

Abstract

The application discloses a preparation method of a beta-trifluoromethyl enamine compound based on organic dye catalysis, belongs to the technical field of medicine, pesticide product and material intermediate synthesis, and the structure of the beta-trifluoromethyl enamine compound is shown as formula I: the preparation method is under the irradiation of environment-friendly green and economic visible light, a catalytic amount of commercialized organic dye Na2-Eosin Y is used as a photocatalyst, cheap and easily obtained, stable and simple-to-operate CF3SO2Na is used as a trifluoromethyl source, Na2CO3 is used as an additive, and t-butyl hydrogen peroxide is used as an initiator. The reaction condition is mild, the reaction is not sensitive to air and water, the operation is simple, the reaction efficiency is high, and the target product is easy to purify. Meanwhile, the application has a wide range of reaction substrates and good functional group tolerance, and most of the target product compounds can be obtained in good to excellent yield.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical, pesticide product and material intermediate synthesis technology. Specifically, it relates to a method for preparing β-trifluoromethylenamine compounds by direct CH trifluoromethylation of enamine and CF3SO2Na as two components under visible light irradiation and with organic dye Na2-Eosin Y as a photosensitive catalyst. Background Technology

[0002] Enamines are unsaturated amines with electron-rich structures containing double bonds, where the carbon atoms are bonded to nitrogen atoms. Due to their interesting redox properties, they can be considered nitrogen-containing enols. Furthermore, enamines are powerful intermediates in organic synthesis, widely used in the synthesis of various organic heterocyclic molecules, including quinolines, pyridines, indoles, and pyrroles, thus providing precursors for a series of biologically active compounds or natural products such as alkaloids, peptides, amino acids, and their derivatives. Therefore, enamines play an important role in the fields of medicine, biology, and synthesis. With in-depth research on enamines by organic chemists, the synthetic methods for these compounds have become increasingly sophisticated, giving rise to a number of simple and reliable synthetic approaches, such as Nair's enamine synthesis, Maurya's enamine synthesis, and Chen's enamine synthesis. Currently, through continuous efforts, organic chemists both domestically and internationally are not only boldly experimenting with new enamine synthetic routes and methods, but also constantly innovating the application of enamines in a wider range of fields.

[0003] As is well known, fluorine (F) is the element with the smallest radius and strongest nonmetallic character in the periodic table. With the development of science and technology, chemists have discovered that organic compounds containing fluorine possess unique physicochemical properties not found in other compounds. Compared to non-fluorinated organic molecules, fluorinated organic molecules exhibit excellent lipophilicity, playing a crucial role in the research and development of organic chemical drugs. The introduction of the CF3 group can significantly influence the properties of organic molecules, thereby increasing their applicability as drugs, agrochemicals, or organic materials. Currently, the direct CH4ization of olefins via visible light catalysis to introduce target groups into organic molecules has become an important method in organic synthesis. The successful introduction of CF3 plays a key role in significantly improving the lipophilicity, acidity, adsorption or absorption properties, and metabolic stability of compounds. Therefore, organic compounds containing CF3 have extremely wide applications in medicine, materials, and pesticides. In recent years, introducing CF3 into target organic compounds in a more environmentally friendly and inexpensive manner has become one of the problems that more and more chemical researchers need to solve.

[0004] Currently, many reliable methods have been established for the direct CH functionalization of alkenes to successfully introduce CF3 into different target organic molecules. For example, under copper catalysis, CH trifluoromethylation of alkenes has been carried out using reagents with different trifluoromethyl sources (Togni reagent, Umemoto reagent, and TMSCF3), but the target products obtained have failed to form C-CF3 bonds in the alkenes. Subsequently, a method using CF3I as a trifluoromethyl source achieved the trifluoromethylation of terminal alkenes under visible light induction. Recently, a transition metal-free enamine CH trifluoromethylation reaction successfully introduced trifluoromethyl groups into enamine double bonds. The above works have all successfully constructed C-CF3 bonds, opening up new possibilities in the field of olefin trifluoromethylation to some extent. However, these methods often involve high-cost and unstable trifluoromethylating reagents, or the use of expensive transition metals as catalysts; some methods require additional heating to start the reaction, which is not feasible from an environmental and economic perspective. Therefore, developing a milder and more environmentally friendly method to introduce CF3 into enamine compounds remains a meaningful endeavor. Summary of the Invention

[0005] To address the aforementioned problems, this invention provides a method for developing a white LED (λ) system in air at room temperature, using readily available and inexpensive enamine as a substrate, CF3SO2Na as a trifluoromethyl source, and the commercially available organic dye Na2-Eosin Y as a catalyst, with tert-butyl hydroperoxide as an initiator additive. max A mild and green method for the one-step preparation of β-trifluoromethylenamine compounds by CH trifluoromethylation of two components, enamine and tri(CF3SO2Na), was successfully achieved under irradiation with a 455nm lamp.

[0006] The technical solution of the present invention is: a one-step photocatalytic method for preparing β-trifluoromethylenamine compounds based on organic dyes as catalysts, as described in the present invention;

[0007] The chemical structure of the β-trifluoromethylenamine compound is shown in Formula I:

[0008]

[0009] Wherein, the R 1 Or R 2 It is any one of hydrogen, long-chain alkyl, cycloalkyl, benzyl, propynyl and their derivative groups;

[0010] The EWG is any one of ester group, carbonyl group, amide group and their derivative groups;

[0011] The specific steps include the following:

[0012] Step 1: Place a polytetrafluoroethylene magnetic stir bar in a dry, clean quartz reaction tube with a stopper, and then add CF3SO2Na, Na2CO3, Na2-Eosin Y and dimethyl sulfoxide solvent to the reaction tube in sequence; stir the reaction mixture at room temperature until it is mixed evenly, then add enamine to the mixture, and finally add tert-butyl hydrogen peroxide to the reaction mixture to obtain the reaction solution;

[0013] Step 2: Under air and at room temperature, stir the prepared reaction solution for 12 hours under the illumination of 10W white LEDs (λmax = 455nm). Monitor the reaction using a TLC plate. Stop the reaction once the enamine raw material has been consumed and disappeared.

[0014] Step 3: Quench the reaction solution in step (2) with deionized water, then transfer it to a separatory funnel and extract it with ethyl acetate. Combine the organic phases, dry them with anhydrous Na2SO4, and filter them. Collect the filtrate in a round-bottom flask and remove the solvent under reduced pressure using a rotary evaporator to obtain a reaction mixture mainly composed of crude trifluoromethylenamine derivatives, namely a mixture of β-trifluoromethylenamine compounds and reaction byproducts.

[0015] Step 4: The mixture of the obtained β-trifluoromethylenamine compound and reaction byproducts was separated and purified using a 300-mesh silica gel column, and then purified using V... 石油醚 V 乙酸乙酯 V 三乙胺 The eluent was a mixture of petroleum ether, ethyl acetate, and triethylamine. The solution containing pure β-trifluoromethylenamine derivatives was collected and transferred to a round-bottom flask. The eluent was removed by rotary evaporation. The mixture was then dried and weighed to obtain a pale yellow or yellow oily or solid compound, which is the β-trifluoromethylenamine compound catalyzed by organic dye.

[0016] Furthermore, in step (1), the polytetrafluoroethylene magnetic stir bar is spindle-shaped, and its measurement unit is 6*10mm; it plays a role in stirring during the reaction, thereby accelerating the reaction and making the reaction complete, but it does not participate in the reaction itself.

[0017] Furthermore, in step (1), the enamine is one of secondary amino acrylate or tertiary amino acrylate;

[0018] Specifically: raw materials (E)-3-(secondary amino)acrylate compound and (E)-3-(tert-amino)ethyl acrylate compound;

[0019] Wherein, the compound structure of the secondary amino acrylate ((E)-3-(secondary amino)acrylate compound) is any one of the following structures:

[0020]

[0021] The compound structure of the tertiary amino acrylate ((E)-3-(tertiary amino)acrylate ethyl acrylate compound) is any one of the following structures:

[0022]

[0023] Furthermore, in step (1), the trifluoromethyl group is derived from Langlois reagent, namely CF3SO2Na, which has the following structure:

[0024]

[0025] Furthermore, in step (1), the quartz tube is made of high-purity quartz powder with a silica content of over 99.9%, and its hardness, light transmittance, and high-temperature resistance are superior to those of ordinary glass reaction tubes.

[0026] Furthermore, in step (1), the amount of Na2-Eosin Y used is 10 mol%.

[0027] The molar ratio of the enamine, CF3SO2Na, Na2CO3, and tert-butyl hydroperoxide is 1:4:3:4.

[0028] The enamine, used as a reaction substrate, is present at a concentration of 0.1 mol / L in the solvent dimethyl sulfoxide.

[0029] The CF3SO2Na used as the trifluoromethyl source in the reaction has a concentration of 0.4 mol / L in the solvent dimethyl sulfoxide.

[0030] The Na2CO3 is used as a reaction additive, and its concentration in the solvent dimethyl sulfoxide is 0.3 mol / L.

[0031] The tert-butyl hydroperoxide is used as a reaction initiator, and its concentration in the solvent dimethyl sulfoxide is 0.4 mol / L.

[0032] Furthermore, the room temperature is 18-33°C.

[0033] Specifically,

[0034] 1. Enamines: These are unsaturated amines with electron-rich structures containing a double bond with the carbon atom of the double bond connected to a nitrogen atom. Because their structure contains a carbon-carbon double bond activated by a nitrogen atom and a nucleophilic amino group, they have many excellent reactivity characteristics, such as (1) the carbon-carbon double bond is activated by a nitrogen atom, which greatly increases the reactivity of the carbon-carbon double bond in enamines, thus making them suitable for preparing various chiral amines and multi-substituted natural amine derivatives; (2) they have multiple nucleophilic or electrophilic centers; (3) in the enamine structure, if the group substituted at one end of the carbon-carbon double bond is an active group, such as halogen, boron, phosphine, silicon, etc. Because enamines have many advantages such as high reactivity and multiple reaction sites, they can be used as a powerful intermediate in organic synthesis, especially in the synthesis of natural products and nitrogen-containing heterocyclic compounds such as quinoline, pyridine, indole, pyrrole, etc., thus providing a series of biologically active compounds or natural products such as alkaloids, peptides or amino acids and their derivatives. Furthermore, enamines themselves possess unique medicinal properties and exist as key structural units in countless natural products and drugs. In summary, enamine compounds are of great significance in the fields of medicine, biology, and synthesis.

[0035] 2. Sodium trifluoromethyl sulfinate (CF3SO2Na): A commercially available trifluoromethyl source reagent. This reagent was first reported by Langlois et al. in 1991, who used it as an electrophilic agent in their research on the trifluoromethylation of aromatic compounds. Compared with other trifluoromethyl source reagents (such as Togni reagent, Umemoto reagent, TMSCF3 reagent, CF3I reagent, etc.), CF3SO2Na is more stable, economical, and easy to operate. In recent years, it has been frequently used as a trifluoromethyl source to introduce trifluoromethyl groups into target compounds, and it has wide applications in the field of synthetic organofluorine chemistry.

[0036] 3. Disodium eosin Y (Na2-Eosin Y): A red fluorescent dye, also known as disodium eosin Y, it dissociates in water into negatively charged anions that can bind to positively charged cations in protein amino groups, thus staining cytoplasm, erythrocytes, collagen, muscle fibers, connective tissue, and eosinophilic granules to varying degrees of red or pink. As an acidic dye, it is commonly used in hematoxylin-eosin staining and as a counterstain for hematoxylin. Staining results in pink to orange-yellow cytoplasm and deep blue or deep purple nuclei. Disodium eosin Y can also be combined with azure II for morphological observation of bone marrow cells. Azure A / eosin Y staining can reveal cell granules, microorganisms, and nucleoli, and can also visualize insect muscle tissue and cells infected with mosquito iridovirus.

[0037] 4. Dimethyl sulfoxide (DMSO): A sulfur-containing organic compound with the molecular formula C₂H₆OS. At room temperature, it is a colorless, odorless, transparent, hygroscopic, and flammable liquid. It possesses high polarity, a high boiling point, good thermal stability, is aprotic, and miscible with water. It is soluble in most organic compounds, including ethanol, propanol, benzene, and chloroform, and is known as a "universal solvent." Heating it in the presence of acid will produce small amounts of compounds such as methyl mercaptan, formaldehyde, dimethyl sulfide, and methanesulfonic acid. Furthermore, it decomposes at high temperatures and reacts violently with chlorine, burning in air with a pale blue flame. It can be used as an organic solvent, reaction medium, and intermediate in organic synthesis. It can also be used as a dyeing solvent, dye remover, dyeing carrier, and absorbent for recovering acetylene and sulfur dioxide in synthetic fibers.

[0038] 5. Tert-Butyl Hydrogen Peroxide (TBHP): An important branch of organic peroxides, this substance is a volatile, slightly yellow, transparent liquid. It is an alkyl hydrogen organic peroxide, also known as tert-butyl hydrogen peroxide. TBHP is slightly soluble in water, readily soluble in most organic solvents such as alcohols and ethers, and in aqueous sodium hydroxide solutions. Its solubility in water is 12%, and it is weakly acidic. It is stable below 75℃, loses oxygen at 95℃-100℃, and explodes at 250℃. It is mainly used as an initiator in polymerization reactions (such as the elimination of monomers after emulsion polymerization of polyvinyl chloride and polyacrylic acid), a crosslinking agent for unsaturated polyesters, in emulsion polymerization, in the vulcanization of natural raw rubber, in diesel additives, and in the paint industry. It is also widely used as a raw material for the synthesis of other organic peroxides.

[0039] 6. Sodium carbonate (Na₂CO₃): An inorganic compound with the chemical formula Na₂CO₃, also known as soda ash, baking soda, or alkali ash. At room temperature, it is a white, odorless powder or granules, hygroscopic, readily soluble in water and glycerol, slightly soluble in anhydrous ethanol, and sparingly soluble in propanol. Its aqueous solution is alkaline and somewhat corrosive. It can undergo double displacement reactions with acids, as well as some calcium and barium salts. The solution is alkaline and turns phenolphthalein red. It is also an important inorganic chemical raw material, mainly used in the production of flat glass, glass products, and ceramic glazes. It is also widely used in household detergents, acid neutralization, and food processing.

[0040] The beneficial effects of the present invention are: (1) The method of the present invention utilizes green and environmentally friendly visible light irradiation, economical, stable and easy-to-operate CF3SO2Na as trifluoromethyl source, and commercially available organic dye Na2-Eosin Y as catalyst to catalyze the one-step reaction of enamine and CF3SO2Na, which efficiently and rapidly prepares β-trifluoromethylenamine compound, which is a derivative intermediate with pharmaceutical value; (2) The method of the present invention is simple to operate, the experimental device is easy to assemble and automate, the substrates and raw materials used are widely available and inexpensive; the reaction conditions are mild and green, and it is not sensitive to air and water, avoiding the use of flammable, explosive and highly polluting organic solvents; it has a wide range of substrates and good functional group tolerance, and can give the target product in high yield. The synthesized β-CF3 substituted enamine is a potential β-amino acid precursor, which makes the β-trifluoromethylenamine compound have greater practical potential in the field of further organic synthesis research. Attached Figure Description

[0041] Figure 1 This is a flowchart illustrating the structure of the present invention. Detailed Implementation

[0042] To more clearly illustrate the technical solution of the present invention, the present invention will be further described below. Obviously, the following description only describes a portion of the embodiments. For those skilled in the art, the technical solution of the present invention can be applied to other similar scenarios without creative effort. To more clearly illustrate the technical solution of the present invention, the technical solution of the present invention will be further described in detail below with reference to the accompanying drawings:

[0043] As shown in the figure; the β-trifluoromethylenamine compound of the present invention has the chemical structure shown in Formula I:

[0044]

[0045] In Equation I, the R 1 Or R 2 It is any one of hydrogen, long-chain alkyl, cycloalkyl, benzyl, propynyl and their derivative groups;

[0046] The EWG is any one of ester group, carbonyl group, amide group and their derivative groups;

[0047] Furthermore, a method for preparing β-trifluoromethylenamine compounds based on organic dye catalysis includes the following specific steps:

[0048] Step 1: Place a polytetrafluoroethylene magnetic stir bar in a dry, clean, stoppered quartz reaction tube, then add sodium trifluoromethanesulfonate (CF3SO2Na), Na2CO3, Na2-Eosin Y, and dimethyl sulfoxide solvent to the reaction tube in sequence; stir the reaction mixture at room temperature until it is homogeneous, then add enamine to the mixture, and finally add tert-butyl hydrogen peroxide to the reaction mixture to obtain the reaction solution;

[0049] Step 2: Under air atmosphere and at room temperature, place the reaction mixture under 10W white LEDs (λ). max The reaction was stirred for 12 hours under irradiation with a 455nm lamp; the reaction was monitored by TLC plate, and the reaction was stopped after the enamine raw material was consumed and disappeared.

[0050] Step 3: Quench the reaction solution in step (2) with deionized water, then transfer it to a separatory funnel and extract it with ethyl acetate. Combine the organic phases, dry them with anhydrous Na2CO3, and filter them. Collect the filtrate in a round-bottom flask and remove the solvent under reduced pressure using a rotary evaporator to prepare a reaction mixture mainly composed of trifluoromethylenamine derivatives, namely a mixture of β-trifluoromethylenamine compounds and reaction byproducts.

[0051] Step 4: The resulting reaction mixture containing β-trifluoromethylenamine derivatives was separated and purified using a 300-mesh silica gel column, and V... 石油醚 V 乙酸乙酯 V 三乙胺 A solution containing pure β-trifluoromethylenamine derivatives was collected using a 16:1:0.5 eluent and transferred to a round-bottom flask. The eluent, a mixture of petroleum ether, ethyl acetate, and triethylamine, was removed using a rotary evaporator. Subsequently, the purified β-trifluoromethylenamine derivatives were dried and weighed, ultimately yielding a pale yellow or yellow oily or solid β-trifluoromethylenamine compound, which is the β-trifluoromethylenamine compound catalyzed by organic dyes.

[0052] Furthermore, the Langlois reagent, a trifluoromethyl source reagent, namely CF3SO2Na, has the following structure:

[0053] Furthermore, in step (1), the polytetrafluoroethylene magnetic stir bar is spindle-shaped, and its measurement unit is 6*10mm; it plays a role in stirring during the reaction, thereby accelerating the reaction and making the reaction complete, but it does not participate in the reaction itself.

[0054] Furthermore, the quartz tube is made of high-purity quartz powder with a silica content of over 99.9%, and its hardness, light transmittance, and high-temperature resistance are superior to those of ordinary glass reaction tubes.

[0055] In step (1), the enamine is one of secondary amino acrylate or tertiary amino acrylate;

[0056] Wherein, the compound structure of the secondary amino acrylate ((E)-3-(secondary amino)acrylate compound) is any one of the following structures:

[0057]

[0058] The compound structure of the tertiary amino acrylate ((E)-3-(tertiary amino)acrylate ethyl acrylate compound) is any one of the following structures:

[0059]

[0060] Furthermore, the Na2-Eosin Y is used as a catalyst at an amount of 10 mol%.

[0061] The molar ratio of the enamine, CF3SO2Na, Na2CO3, and tert-butyl hydroperoxide is 1:4:3:4.

[0062] The enamine, used as a reaction substrate, is present at a concentration of 0.1 mol / L in the solvent dimethyl sulfoxide.

[0063] The CF3SO2Na used as the trifluoromethyl source in the reaction has a concentration of 0.4 mol / L in the solvent dimethyl sulfoxide.

[0064] The Na2CO3 is used as a reaction additive, and its concentration in the solvent dimethyl sulfoxide is 0.3 mol / L.

[0065] Furthermore, the room temperature is 18-33℃.

[0066] Example 1:

[0067] β-Trifluoromethylenamine compounds

[0068] Synthesis of 2-chlorobenzyl(E)-3-(benzylamino)-2-(trifluoromethyl)acrylate:

[0069]

[0070] A polytetrafluoroethylene magnet was added to a dry and clean 10 mL quartz tube, followed by the sequential addition of CF3SO2Na (312.1 mg, 2.0 mmol), Na2CO3 (158.9 mg, 1.5 mmol), Na2-Eosin Y (0.05 mmol, 10 mol%), and dimethyl sulfoxide (5.0 mL) solvent. After stirring and mixing thoroughly, 2-chlorobenzyl(E)-3-(benzylamino)-2-(trifluoromethyl)acrylate (140.1 mg, 0.5 mmol) was added, and finally tert-butyl hydroperoxide (192.4 μL, 2.0 mmol) was added to prepare the reaction solution.

[0071] In an empty atmosphere at room temperature, a quartz tube containing the reaction solution was placed under 10W white LEDs (λ). max The reaction was stirred for 12 hours under irradiation with a 455nm lamp and monitored by TLC plate. The reaction was stopped when the 2-chlorobenzyl(E)-3-(benzylamino)acrylate raw material was consumed and disappeared.

[0072] The reaction was quenched with deionized water, then transferred to a separatory funnel and extracted with ethyl acetate. The organic phases were combined, dried over anhydrous Na2SO4, and filtered. The filtrate was collected in a round-bottom flask and then the ethyl acetate was removed under reduced pressure using a rotary evaporator to obtain a reaction mixture mainly composed of (E)-3-(primary amino)-2-(trifluoromethyl)acrylate derivatives, namely 2-chlorobenzyl(E)-3-(benzylamino)-2-(trifluoromethyl)acrylate and a mixture of reaction byproducts.

[0073] The resulting reaction mixture containing 2-chlorobenzyl(E)-3-(benzylamino)-2-(trifluoromethyl)acrylate was purified by chromatography using a 300-mesh silica gel column with ethyl acetate. 石油醚 :V 乙酸乙酯 :V 三乙胺 The column chromatography was performed using a 16:1:0.5 eluent. The solution containing pure 2-chlorobenzyl(E)-3-(benzylamino)-2-(trifluoromethyl)acrylate was collected and transferred to a round-bottom flask. The eluent, a mixture of ethyl acetate, petroleum ether, and triethylamine, was removed by rotary evaporation to obtain pure 2-chlorobenzyl(E)-3-(benzylamino)-2-(trifluoromethyl)acrylate. Subsequently, it was dried and weighed to obtain 171.6 mg of pure yellow oily 2-chlorobenzyl(E)-3-(benzylamino)-2-(trifluoromethyl)acrylate, which is the method for preparing β-trifluoromethylenamine compounds based on organic dye catalysis. The yield of the product 2-chlorobenzyl(E)-3-(benzylamino)-2-(trifluoromethyl)acrylate was 93%.

[0074] Identification data of the product in this embodiment:

[0075] 1 H NMR(400MHz,DMSO-d6)δ9.11(dt,J=13.3,6.2Hz,1H),7.84(d,J=14.1Hz,1H ),7.52-7.42(m,2H),7.42-7.26(m,7H),5.27(s,2H),4.56(d,J=6.2Hz,2H). 19 F NMR(376MHz,DMSO-d6)δ-56.20. 13 C NMR(101MHz,DMSO-d6)δ165.2,154.2(q,J=5.7Hz),138.6,134.1,132.1,129.7,129.3,129.1,128.7, 127.5(2C),127.4,125.7(q,J=265.5Hz),84.65(q,J=31.9Hz),62.0,51.8.HR-MS(ESI),m / z(%):Calcd for C 18 H 15 ClF3NNaO2 + [M+Na] + :392.0636,Found:392.0635.

[0076] Example 2:

[0077] β-Trifluoromethylenamine compounds

[0078] Synthesis of Ethyl(E)-3-(sec-butylamino)-2-(trifluoromethyl)acrylate:

[0079]

[0080] A polytetrafluoroethylene magnet was added to a dry and clean 10 mL quartz tube, followed by the sequential addition of CF3SO2Na (312.1 mg, 2.0 mmol), Na2CO3 (158.9 mg, 1.5 mmol), Na2-Eosin Y (0.05 mmol, 10 mol%), and dimethyl sulfoxide (5.0 mL) solvent. After stirring and mixing thoroughly, ethyl (E)-3-(sec-butylamino)acrylate (85.6 mg, 0.5 mmol) was added, and finally tert-butyl hydroperoxide (192.4 μL, 2.0 mmol) was added to prepare the reaction solution.

[0081] In an empty atmosphere at room temperature, a quartz tube containing the reaction solution was placed under 10W white LEDs (λ). maxThe reaction was stirred for 12 hours under irradiation with a 455nm lamp and the reaction was monitored by TLC plate. The reaction was stopped when the (E)-3-(sec-butylamino) ethyl acrylate raw material was consumed and disappeared.

[0082] The reaction was quenched by washing with deionized water, then transferred to a separatory funnel and extracted with ethyl acetate. The organic phases were combined, dried over anhydrous Na2SO4, filtered, and the filtrate was collected in a round-bottom flask and the ethyl acetate was removed under reduced pressure using a rotary evaporator to obtain a reaction mixture mainly composed of (E)-3-(primary amino)-2-(trifluoromethyl)acrylate, namely, a mixture of (E)-3-(sec-butylamino)-2-(trifluoromethyl)acrylate compound and reaction byproducts.

[0083] The resulting reaction mixture containing (E)-3-(sec-butylamino)-2-(trifluoromethyl)acrylate was purified by chromatography using a 300-mesh silica gel column, with V 石油醚 :V 乙酸乙酯 :V 三乙胺 The column chromatography was performed using a 16:1:0.5 eluent. The solution containing pure (E)-3-(sec-butylamino)-2-(trifluoromethyl)acrylate was collected and transferred to a round-bottom flask. The eluent, a mixture of ethyl acetate, petroleum ether, and triethylamine, was removed by rotary evaporation to obtain pure (E)-3-(sec-butylamino)-2-(trifluoromethyl)acrylate. Subsequently, it was dried and weighed to obtain 109.9 mg of pure, light yellow, oily (E)-3-(sec-butylamino)-2-(trifluoromethyl)acrylate, which is the method for preparing β-trifluoromethylenamine compounds based on organic dye catalysis. The yield of the product (E)-3-(sec-butylamino)-2-(trifluoromethyl)acrylate was 92%.

[0084] Identification data of the product in this embodiment:

[0085] 1 H NMR(400MHz,DMSO-d6,Major isomer)δ8.58(dd,J=14.2,8.5Hz,1H),7.63(d,J=14.0Hz,1H),4.15(q,J=7.1Hz,2H) ,3.51-3.39(m,1H),1.52(p,J=7.3Hz,2H),1.24-1.16(m,6H),0.85(t,J=7.4Hz,3H). 19 F NMR (376MHz, DMSO-d6, Major isomer, E / Z≈60 / 1)δ-56.30. 13C NMR(101MHz,DMSO-d6,Major isomer)δ166.6,152.9(q,J=5.7Hz),126.2(q,J=265.4Hz),84.70(q,J=31.8Hz),59.5,56.7,30.0,21.3,14.7,10.5.HR-MS(ESI),m / z(%):Calcd for C 10 H 16 F3NNaO2 + [M+Na] + :316.1519,Found:262.1017.

[0086] Example 3:

[0087] β-Trifluoromethylenamine compounds

[0088] Synthesis of Ethyl(E)-3-(dibenzylamino)-2-(trifluoromethyl)acrylate:

[0089]

[0090] A polytetrafluoroethylene magnet was added to a dry and clean 10 mL quartz tube, followed by the sequential addition of CF3SO2Na (312.1 mg, 2.0 mmol), Na2CO3 (158.9 mg, 1.5 mmol), Na2-Eosin Y (0.05 mmol, 10 mol%), and dimethyl sulfoxide (5.0 mL) solvent. After stirring and mixing thoroughly, ethyl (E)-3-(dibenzylamino)acrylate (147.6 mg, 0.5 mmol) was added, and finally tert-butyl hydroperoxide (192.4 μL, 2.0 mmol) was added to prepare the reaction solution.

[0091] In an empty atmosphere at room temperature, a quartz tube containing the reaction solution was placed under 10W white LEDs (λ). max The reaction was stirred for 12 hours under irradiation at 455 nm and monitored by TLC plate. The reaction was stopped when the (E)-3-(dibenzylamino) ethyl acrylate raw material was consumed and disappeared.

[0092] The reaction mixture was quenched with deionized water, then transferred to a separatory funnel and extracted with ethyl acetate. The organic phases were combined, dried over anhydrous Na2SO4, filtered, and the filtrate was collected in a round-bottom flask and the ethyl acetate was removed under reduced pressure using a rotary evaporator to obtain a reaction mixture mainly composed of (E)-3-(tert-amino)-2-(trifluoromethyl)acrylate derivatives, namely, a mixture of (E)-3-(dibenzylamino)-2-(trifluoromethyl)acrylate compound and reaction byproducts.

[0093] The resulting reaction mixture containing (E)-3-(dibenzylamino)-2-(trifluoromethyl)acrylate was separated and purified using a 300-mesh silica gel column, with V 石油醚 :V 乙酸乙酯 :V 三乙胺 The column chromatography was performed using a 16:1:0.5 eluent. The solution containing pure (E)-3-(dibenzylamino)-2-(trifluoromethyl)acrylate was collected and transferred to a round-bottom flask. The eluent, a mixture of ethyl acetate, petroleum ether, and triethylamine, was removed by rotary evaporation to obtain pure (E)-3-(dibenzylamino)-2-(trifluoromethyl)acrylate. Subsequently, it was dried and weighed to obtain 148.9 mg of pure, light yellow, oily (E)-3-(dibenzylamino)-2-(trifluoromethyl)acrylate, which is the method for preparing β-trifluoromethylenamine compounds based on organic dye catalysis. The yield of the product (E)-3-(dibenzylamino)-2-(trifluoromethyl)acrylate was 82%.

[0094] Identification data of the product in this embodiment:

[0095] 1 H NMR (400MHz, DMSO-d6, Major isomer) δ7.59 (d, J = 4Hz, 1H), 7.38-7.28 (m, 6H), 7.23-7.19 (m, 4H) 4.60 (s, 4H), 3.97 (q, J = 7.1Hz, 2H), 1.04 (t, J = 7.1Hz, 3H). 19 F NMR (376MHz, DMSO-d6, Major isomer, E / Z≈10 / 1)δ-55.38. 13 C NMR (100MHz, DMSO-d6, Majorisomer) δ163.4,150.5(q,J=6.5Hz),129.4,129.2(q,J=268 .7Hz),129.1,128.1,128.0,89.4(q,J=29.8Hz),60.1,14.5.HR-MS(ESI),m / z(%):Calcd for C 20 H 21 F3NO2 + [M+H] + :364.1519,Found:364.1516.

[0096] Example 4:

[0097] β-Trifluoromethylenamine compounds

[0098] Synthesis of Ethyl(E)-3-(dipropylamino)-2-(trifluoromethyl)acrylate

[0099]

[0100] A polytetrafluoroethylene magnet was added to a dry and clean 10 mL quartz tube, followed by the sequential addition of CF3SO2Na (312.1 mg, 2.0 mmol), Na2CO3 (158.9 mg, 1.5 mmol), Na2-Eosin Y (0.05 mmol, 10 mol%), and dimethyl sulfoxide (5.0 mL) solvent. The mixture was stirred until homogeneous, and then ethyl (E)-3-(dipropylamino)acrylate (99.6 mg, 0.5 mmol) was added. Finally, tert-butyl hydroperoxide (192.4 μL, 2.0 mmol) was added to obtain the reaction solution.

[0101] In an empty atmosphere at room temperature, a quartz tube containing the reaction solution was placed under 10W white LEDs (λ). max The reaction was stirred for 12 hours under irradiation at 455 nm and the reaction was monitored by TLC plate. The reaction was stopped when the (E)-3-(dipropylamino)acrylate raw material was consumed and lost.

[0102] The reaction was quenched with deionized water, then transferred to a separatory funnel and extracted with ethyl acetate. The organic phases were combined, dried over anhydrous Na2SO4, filtered, and the filtrate was collected in a round-bottom flask and the ethyl acetate was removed under reduced pressure using a rotary evaporator to obtain a reaction mixture mainly composed of (E)-3-(tert-amino)-2-(trifluoromethyl)acrylate derivatives, namely, a mixture of (E)-3-(dipropylamino)-2-(trifluoromethyl)acrylate compound and reaction byproducts.

[0103] The resulting reaction mixture containing (E)-3-(dipropylamino)-2-(trifluoromethyl)acrylate was separated and purified using a 300-mesh silica gel column, and then purified using V... 石油醚 :V 乙酸乙酯 :V 三乙胺The solution containing pure (E)-3-(dipropylamino)-2-(trifluoromethyl)acrylate ethyl ester was collected and transferred to a round-bottom flask using a column eluent of 16:1:0.5. The eluent, a mixture of ethyl acetate, petroleum ether, and triethylamine, was removed by rotary evaporation to obtain pure (E)-3-(dipropylamino)-2-(trifluoromethyl)acrylate. The solution was then dried and weighed to obtain 116.2 mg of pure, pale yellow, oily (E)-3-(dipropylamino)-2-(trifluoromethyl)acrylate, which is the method for preparing β-trifluoromethylenamine compounds based on organic dye catalysis. The yield of the product (E)-3-(dipropylamino)-2-(trifluoromethyl)acrylate was 87%.

[0104] Identification data of the product in this embodiment:

[0105] 1 H NMR(400MHz, DMSO-d6, Major isomer)δ7.17(d,J=1.1Hz,1H),4.09(q,J=7.1Hz,2H),3.35-3.31(t,J=7.3Hz,4H,containing one water peak), 1.50-1.46 (m, 4H), 1.17 (t, J = 7.1Hz, 3H), 0.79 (t, J = 7.4Hz, 6H). 19 F NMR (376MHz, DMSO-d6, Major isomer, E / Z≈6.5 / 1)δ-54.84. 13 C NMR (101MHz, DMSO-d6, Major isomer)δ163.0,149.3(q,J=6.2Hz),126.44(q,J=268.9Hz),86.07(q,J=29.7Hz),59.31,14.23,10.51.HR-MS(ESI),m / z(%):Calcd for C 12 H 20 F3NO2Na + [M+Na] + :290.1338,Found:290.1347.

[0106] Example 5:

[0107] Synthesis of β-trifluoromethylenamine compound tetrahydrofuran-2-yl methyl(E)-3-(dipropylamino)-2-(trifluoromethyl)acrylate

[0108]

[0109] A polytetrafluoroethylene magnet was added to a dry and clean 10 mL quartz tube, followed by the sequential addition of CF3SO2Na (312.1 mg, 2.0 mmol), Na2CO3 (158.9 mg, 1.5 mmol), Na2-Eosin Y (0.05 mmol, 10 mol%), and dimethyl sulfoxide (5.0 mL) solvent. The mixture was stirred until homogeneous, and then (tetrahydrofuran-2-yl)methyl(E)-3-(dipropylamino)acrylate (127.6 mg, 0.5 mmol) was added. Finally, tert-butyl hydroperoxide (192.4 μL, 2.0 mmol) was added to obtain the reaction solution.

[0110] In an air atmosphere at room temperature, a quartz tube containing the reaction solution was placed under 10W white LEDs (λmax=455nm) and stirred for 12 hours. The reaction was monitored by a TLC plate. The reaction was stopped when the (tetrahydrofuran-2-yl)methyl(E)-3-(dipropylamino)acrylate raw material was consumed and disappeared.

[0111] The reaction was quenched with deionized water, then transferred to a separatory funnel and extracted with ethyl acetate. The organic phases were combined, dried over anhydrous Na2SO4, and filtered. The filtrate was collected in a round-bottom flask and the ethyl acetate was removed under reduced pressure using a rotary evaporator, thus obtaining a reaction mixture mainly composed of (E)-3-(tert-amino)-2-(trifluoromethyl)acrylate derivatives, namely a mixture of (tetrahydrofuran-2-yl)methyl(E)-3-(dipropylamino)-2-(trifluoromethyl)acrylate compounds and reaction byproducts.

[0112] The resulting reaction mixture containing (tetrahydrofuran-2-yl)methyl(E)-3-(dipropylamino)-2-(trifluoromethyl)acrylate was separated and purified using a 300-mesh silica gel column, and then purified using V... 石油醚 :V 乙酸乙酯 :V 三乙胺The solution containing pure (tetrahydrofuran-2-yl)methyl(E)-3-(dipropylamino)-2-(trifluoromethyl)acrylate was collected and transferred to a round-bottom flask. The eluent, a mixture of ethyl acetate, petroleum ether, and triethylamine, was removed by rotary evaporation to obtain pure (tetrahydrofuran-2-yl)methyl(E)-3-(dipropylamino)-2-(trifluoromethyl)acrylate. The solution was then dried and weighed to obtain 122.8 mg of pure, pale yellow, oily (tetrahydrofuran-2-yl)methyl(E)-3-(dipropylamino)-2-(trifluoromethyl)acrylate, which is the method for preparing β-trifluoromethylenamine compounds based on organic dye catalysis. The yield of the product (tetrahydrofuran-2-yl)methyl(E)-3-(dipropylamino)-2-(trifluoromethyl)acrylate was 76%.

[0113] Identification data of the product in this embodiment:

[0114] 1 H NMR(400MHz,DMSO-d6,Major isomer)δ7.20(s,1H),4.02-3.99(m,3H),3.75-3.60(m,2H),3.34(t,J=7.6Hz,4H),1.95-1.74(m,3H),1.63-1.48(m,5H),0.85-0.78(m,6H). 19 F NMR (376MHz, DMSO-d6, Major isomer, E / Z≈5 / 1)δ-54.73. 13 C NMR(101MHz,DMSO-d6,Major isomer)δ162.8,149.8(q,J=6.4Hz),126.4(q,J=268.0Hz),85.7(q,J=29.6Hz),75.9,67.5,65.4,27.5,25.2,10.5.HR-MS(ESI),m / z(%):Calcd for C 15 H 25 F3NO3 + [M+H] + :324.1781,Found:324.1792.

[0115] Example 6:

[0116] β-Trifluoromethylenamine compounds

[0117] Synthesis of 2-chlorobenzyl(E)-3-(dipropylamino)-2-(trifluoromethyl)acrylate

[0118]

[0119] A polytetrafluoroethylene magnet was added to a dry and clean 10 mL quartz tube, followed by the sequential addition of CF3SO2Na (312.1 mg, 2.0 mmol), Na2CO3 (158.9 mg, 1.5 mmol), Na2-Eosin Y (0.05 mmol, 10 mol%), and dimethyl sulfoxide (5.0 mL) solvent. After stirring and mixing thoroughly, 2-chlorobenzyl(E)-3-(dipropylamino)acrylate (147.6 mg, 0.5 mmol) was added, and finally tert-butyl hydroperoxide (192.4 μL, 2.0 mmol) was added to prepare the reaction solution.

[0120] In an empty atmosphere at room temperature, a quartz tube containing the reaction solution was placed under 10W white LEDs (λ). max The reaction was stirred for 12 hours under irradiation at 455 nm and the reaction was monitored by TLC plate. The reaction was stopped when the 2-chlorobenzyl(E)-3-(dipropylamino)acrylate raw material was consumed and disappeared.

[0121] The reaction was quenched with deionized water, then transferred to a separatory funnel and extracted with ethyl acetate. The organic phases were combined, dried over anhydrous Na2SO4, filtered, and the filtrate was collected in a round-bottom flask and the ethyl acetate was removed under reduced pressure using a rotary evaporator to obtain a reaction mixture mainly composed of (E)-3-(tert-amino)-2-(trifluoromethyl)acrylate derivatives, namely a mixture of 2-chlorobenzyl(E)-3-(dipropylamino)-2-(trifluoromethyl)acrylate compounds and reaction byproducts.

[0122] The resulting reaction mixture containing 2-chlorobenzyl(E)-3-(dipropylamino)-2-(trifluoromethyl)acrylate was separated and purified using a 300-mesh silica gel column, and then purified using V... 石油醚 :V 乙酸乙酯 :V 三乙胺The column chromatography was performed using a 16:1:0.5 eluent. The solution containing pure 2-chlorobenzyl(E)-3-(dipropylamino)-2-(trifluoromethyl)acrylate was collected and transferred to a round-bottom flask. The eluent, a mixture of ethyl acetate, petroleum ether, and triethylamine, was removed by rotary evaporation to obtain pure 2-chlorobenzyl(E)-3-(dipropylamino)-2-(trifluoromethyl)acrylate. Subsequently, it was dried and weighed to obtain 126.0 mg of pure, pale yellow, oily 2-chlorobenzyl(E)-3-(dipropylamino)-2-(trifluoromethyl)acrylate, which is the method for preparing β-trifluoromethylenamine compounds based on organic dye catalysis. The yield of the product 2-chlorobenzyl(E)-3-(dipropylamino)-2-(trifluoromethyl)acrylate was 75%.

[0123] Identification data of the product in this embodiment:

[0124] 1 H NMR(400MHz,DMSO-d6,Major isomer)δ7.47-7.41(m,2H),7.35-7.30(m,2H),7.23(s,1H),5.17(s,2H),3.31(d,J=7.3Hz,4H),1.60-1.29(m,4H),0.84-0.64(m,6H). 19 FNMR(376MHz,DMSO-d6,Major isomer,E / Z≈5 / 1)δ-54.47. 13 C NMR(101MHz,DMSO-d6,Majorisomer)δ162.3,150.46(q,J=6.2Hz),134.0,132.3,129.7,129.6,1 29.3,127.3,126.5(q,J=267.8Hz),85.14(q,J=29.9Hz),62.3,10.5.HR-MS(ESI),m / z(%):Calcd forC 17 H 22 ClF3NO2 + [M+H] + :364.1286,Found:364.1286.

[0125] Example 7:

[0126] β-Trifluoromethylenamine compounds

[0127] Synthesis of Phenyl(E)-3-(dipropylamino)-2-(trifluoromethyl)acrylate

[0128]

[0129] A polytetrafluoroethylene magnet was added to a dry and clean 10 mL quartz tube, followed by the sequential addition of CF3SO2Na (312.1 mg, 2.0 mmol), Na2CO3 (158.9 mg, 1.5 mmol), Na2-Eosin Y (0.05 mmol, 10 mol%), and dimethyl sulfoxide (5.0 mL) solvent. After stirring and mixing thoroughly, (E)-3-(dipropylamino)phenyl acrylate (123.6 mg, 0.5 mmol) was added, and finally tert-butyl hydroperoxide (192.4 μL, 2.0 mmol) was added to prepare the reaction solution.

[0130] In an empty atmosphere at room temperature, a quartz tube containing the reaction solution was placed under 10W white LEDs (λ). max The reaction was stirred for 12 hours under irradiation at 455 nm and monitored by TLC plate. The reaction was stopped when the (E)-3-(dipropylamino)phenyl acrylate raw material was consumed and disappeared.

[0131] The reaction was quenched with deionized water, then transferred to a separatory funnel and extracted with ethyl acetate. The organic phases were combined, dried over anhydrous Na2SO4, filtered, and the filtrate was collected in a round-bottom flask and the ethyl acetate was removed under reduced pressure using a rotary evaporator to obtain a reaction mixture mainly composed of (E)-3-(tert-amino)-2-(trifluoromethyl)acrylate derivatives, namely a mixture of (E)-3-(dipropylamino)-2-(trifluoromethyl)acrylate compound and reaction byproducts.

[0132] The resulting reaction mixture containing (E)-3-(dipropylamino)-2-(trifluoromethyl)phenyl acrylate was separated and purified using a 300-mesh silica gel column, and then purified using V... 石油醚 :V 乙酸乙酯 :V 三乙胺 The column chromatography was performed using a 16:1:0.5 eluent. The solution containing pure (E)-3-(dipropylamino)-2-(trifluoromethyl)phenyl acrylate was collected and transferred to a round-bottom flask. The eluent, a mixture of ethyl acetate, petroleum ether, and triethylamine, was removed by rotary evaporation to obtain pure (E)-3-(dipropylamino)-2-(trifluoromethyl)phenyl acrylate. Subsequently, it was dried and weighed to obtain 148.0 mg of pure light yellow oily (E)-3-(dipropylamino)-2-(trifluoromethyl)phenyl acrylate, which is the method for preparing β-trifluoromethylenamine compounds based on organic dye catalysis. The yield of the product (E)-3-(dipropylamino)-2-(trifluoromethyl)phenyl acrylate was 94%.

[0133] Identification data of the product in this embodiment:

[0134] 1 H NMR (400MHz, DMSO-d6, Major isomer) δ7.47-7.35(m,3H),7.24(t,J=7.4Hz,1H),7.05(d,J=7.9Hz,2H),3.40(m,4H),1.69-1.44(m,4H),0.91-0.76(m,6H). 19 F NMR (376MHz, DMSO-d6, Major isomer, E / Z≈6 / 1)δ-54.42. 13 C NMR (101MHz, DMSO-d6, Majorisomer) δ161.1, 151.4 (d, J = 6.4Hz), 150.6, 129.5, 126.4 (d,J=268.4Hz),125.5,121.8,84.7(d,J=30.0Hz),10.52.HR-MS(ESI),m / z(%):Calcd for C 16 H 21 F3NO2 + [M+H] + :316.1519,Found:316.1522.

[0135] The enamine substrates used in the embodiments of this invention are not limited to aliphatic chain amines, benzylamines, or propargylamines as the amine source. Furthermore, when the amine source is tetrahydropyrrole, morpholine, tetrahydropyridine, or compounds with substituent groups at different positions, these compounds can still be used as reaction substrates, and the reaction can proceed smoothly and yield the target product in a high yield. In addition, in the acetylacetyl ester substrates, the ester moiety of the substituent group is not limited to alkyl esters or benzyl esters. When the carbonyl group or amide is a substituent group, these compounds can still be used as substrates for this reaction and yield the target product in a satisfactory yield.

[0136] Finally, it should be understood that the embodiments described in this invention are only used to illustrate the principles of the embodiments of this invention; other variations may also fall within the scope of this invention; therefore, as examples rather than limitations, alternative configurations of the embodiments of this invention can be regarded as consistent with the teachings of this invention; correspondingly, the embodiments of this invention are not limited to the embodiments explicitly introduced and described in this invention.

Claims

1. A method for preparing β-trifluoromethylenamine compounds based on organic dye catalysis, characterized in that, The specific steps include the following: Step 1: Place a polytetrafluoroethylene magnetic stir bar into a quartz reaction tube, and then add CF3SO2Na, Na2CO3, Na2-Eosin Y and dimethyl sulfoxide solvent to the quartz reaction tube in sequence; after stirring and mixing evenly at room temperature, add enamine and tert-butyl hydrogen peroxide to obtain the reaction solution. Step 2: Under air atmosphere and room temperature, irradiate the prepared reaction solution under a 10W white LED light and stir for 12 hours. Monitor the reaction by TLC plate. Stop the reaction after the enamine in the reaction solution is consumed and disappears. Step 3: Quench the reaction solution in step (2) with deionized water, then transfer it to a separatory funnel and extract it with ethyl acetate. Combine the organic phases, dry them with anhydrous Na2SO4, and filter them. Collect the filtrate in a round-bottom flask and remove ethyl acetate under reduced pressure using a rotary evaporator to prepare a reaction mixture mainly composed of trifluoromethylenamine derivatives, namely a mixture of β-trifluoromethylenamine compounds and reaction byproducts. Step 4: The mixture of the obtained β-trifluoromethylenamine compound and reaction byproducts was separated and purified using a 300-mesh silica gel column, and then purified using V... 石油醚 V 乙酸乙酯 V 三乙胺 The eluent was a mixture of petroleum ether, ethyl acetate, and triethylamine. The solution containing the pure β-trifluoromethylenamine derivative was collected and transferred to a round-bottom flask. The eluent was removed by rotary evaporation. The purified β-trifluoromethylenamine derivative was then dried and weighed to obtain a light yellow or yellow oily or solid β-trifluoromethylenamine compound, which is the β-trifluoromethylenamine compound based on organic dye catalysis. In step (1), the enamine is one of secondary amino acrylate or tertiary amino acrylate; The secondary amino acrylate has a compound structure that is any one of the following: The tertiary amino acrylate has any one of the following structures: In step (1), the amount of Na2-Eosin Y used is 10 mol%. The molar ratio of the enamine, CF3SO2Na, Na2CO3, and tert-butyl hydroperoxide is 1:4:3:

4. The concentration of the enamine in the solvent dimethyl sulfoxide is 0.1 mol / L; The concentration of CF3SO2Na in the solvent dimethyl sulfoxide is 0.4 mol / L; The concentration of Na2CO3 in the solvent dimethyl sulfoxide is 0.3 mol / L; The concentration of the tert-butyl hydroperoxide in the solvent dimethyl sulfoxide is 0.4 mol / L.

2. The method for preparing β-trifluoromethylenamine compounds based on organic dye catalysis according to claim 1, characterized in that, In step (1), the polytetrafluoroethylene magnetic stir bar is spindle-shaped and its measurement unit is 6*10mm.

3. The method for preparing β-trifluoromethylenamine compounds based on organic dye catalysis according to claim 1, characterized in that, The room temperature is 18-33℃.

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