A method for trifluoromethylation of olefins
By using hydroxylamine as an initiator and a trifluoromethylating agent in a solvent, the challenge of synthesizing Cvinyl-CF3 compounds via nonmetal-promoted olefin trifluoromethylation was solved, achieving efficient synthesis under mild conditions and improving reaction efficiency and yield.
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Patents(China)
- Current Assignee / Owner
- TSINGHUA UNIVERSITY
- Filing Date
- 2023-11-29
- Publication Date
- 2026-05-26
AI Technical Summary
There are few existing methods for synthesizing Cvinyl-CF3 compounds by non-metal-promoted olefin trifluoromethylation, and it is difficult to achieve efficient synthesis under mild conditions.
Hydroxylamine is used as an initiator, and a trifluoromethylating agent is combined with an olefin to react in a solvent. The trifluoromethylation of the olefin is promoted by nonmetals under mild conditions, and the electron-donating ability of hydroxylamine is enhanced by using basic substances to promote the addition of trifluoromethyl radicals to the olefin.
Efficient trifluoromethylation of olefins was achieved under mild conditions, improving reaction yield and selectivity, simplifying the operation process, and reducing costs.
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Abstract
Description
Technical Field
[0001] This invention relates to the field of organic synthesis, and more specifically, to a method for the trifluoromethylation of olefins. Background Technology
[0002] Olefins are an important class of chemical raw materials containing carbon-carbon double bonds. Through the β-C(sp) bond of olefins... 2 Direct trifluoromethylation of )-H can directly and efficiently construct C vinyl The -CF3 structural unit, which regulates the lipophilicity, binding selectivity, and metabolic stability of organic compounds, is of great significance for the synthesis of bioactive molecules. Currently, various methods have been developed to achieve C... vinyl Synthesis of β-CF3 compounds, for example: (1) Pd(II)-catalyzed coupling reactions of aryl halides with 1-iodo-3,3,3-trifluoropropane and 2-(trifluoromethyl)-acrylic acid; (2) Cu(I)-catalyzed reactions of vinylboric acid with Ruppert-Prakash reagent (TMSCF3) and Langlois reagent (CF3SO2Na); (3) CuCF3-mediated trifluoromethylation of alkynes or alkenyl halides; (4) Ir(III)-catalyzed reactions of alkenes with trifluoromethyl halides, etc. Although metal-catalyzed β-C(sp)-C ... 2 Significant progress has been made in the direct trifluoromethylation of α-H-hydroxyl groups; however, the synthesis of C-hydroxyl groups from nonmetal-promoted olefins via trifluoromethylation remains challenging. vinyl Methods involving -CF3 compounds are still rarely reported. Therefore, developing a non-metal-promoted method for the trifluoromethylation of olefins is of great significance. Summary of the Invention
[0003] This invention is based on the inventors' discoveries and understanding of the following facts and problems: Although metal-catalyzed olefin β-C(sp...) 2 Significant progress has been made in the direct trifluoromethylation of α-H-hydroxyl groups; however, the synthesis of C-hydroxyl groups from nonmetal-promoted olefins via trifluoromethylation remains challenging. vinyl There are still few research reports on the CF3 compound method.
[0004] This invention aims to at least partially solve one of the technical problems in related technologies. To this end, embodiments of this invention propose a method for the trifluoromethylation of olefins, using hydroxylamine as an initiator, and employing nonmetallic promoters to promote the trifluoromethylation of olefins under mild conditions.
[0005] This invention provides a method for trifluoromethylation of an olefin, comprising: reacting an olefin of formula (1), a trifluoromethylating agent, and a hydroxylamine in a solvent to obtain a trifluoromethylated olefin product of formula (2):
[0006]
[0007] The advantages and technical effects of the olefin trifluoromethylation method in this invention are that hydroxylamine is used as an initiator, and non-metallic materials promote the trifluoromethylation of olefins under mild conditions.
[0008] In some embodiments, the hydroxylamine comprises at least one of the following structural formulas:
[0009]
[0010] In some embodiments, the trifluoromethylating agent comprises at least one of the following structural formulas:
[0011]
[0012] In some embodiments, the olefin represented by formula (1) is a terminal olefin or an internal olefin;
[0013] And / or, the olefin shown in formula (1) is an unactivated olefin or an activated olefin.
[0014] In some embodiments, R1, R2, and R3 in the olefin represented by formula (1) are each independently selected from hydrogen or non-hydrogen substituents.
[0015] In some embodiments, the reaction further includes a base, wherein the olefin represented by formula (1), the trifluoromethylating agent, the hydroxylamine and the base are reacted in a solvent to obtain the trifluoromethylated product of the olefin represented by formula (2); preferably, the base includes at least one of sodium carbonate, potassium carbonate, calcium carbonate, potassium fluoride, potassium bicarbonate, sodium bicarbonate, sodium monohydrogen phosphate, sodium dihydrogen phosphate and calcium fluoride.
[0016] In some embodiments, the molar ratio of the olefin, the trifluoromethylating agent, and the hydroxylamine is 1-100:1-4:0.5-4.
[0017] In some embodiments, the molar ratio of the olefin to the base is 1-100:0-4.
[0018] In some embodiments, the reaction temperature is 86-150°C;
[0019] And / or, the reaction time is 7-72 hours;
[0020] And / or, the reaction is carried out in an inert gas atmosphere.
[0021] In some embodiments, the reaction includes: performing a first-stage reaction at a first temperature, and then heating to a second temperature to perform a second-stage reaction to obtain a trifluoromethylated product of an olefin as shown in formula (2);
[0022] Preferably, the temperature of the first stage reaction is 60-85℃; the reaction time of the first stage reaction is 1-6h; the temperature of the second stage reaction is 140-170℃; and the reaction time of the second stage reaction is 7-72h.
[0023] In some embodiments, the solvent includes at least one selected from acetonitrile, tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, dimethyl sulfoxide, ethylene glycol dimethyl ether, and ethylene glycol monomethyl ether. Detailed Implementation
[0024] The embodiments of the present invention are described in detail below. These embodiments are exemplary and intended to explain the present invention, and should not be construed as limiting the present invention.
[0025] An embodiment of the present invention provides a method for the trifluoromethylation of an olefin, comprising: reacting an olefin of formula (1), a trifluoromethylating agent, and hydroxylamine in a solvent to obtain a trifluoromethylated olefin product of formula (2):
[0026]
[0027] The trifluoromethylation method for olefins in this embodiment of the invention uses hydroxylamine as an initiator and nonmetals promote the trifluoromethylation of olefins under mild conditions.
[0028] In some embodiments, the hydroxylamine comprises at least one of the following structural formulas:
[0029]
[0030] Preferably, diethylhydroxylamine (Et2NOH):
[0031]
[0032] In this embodiment of the invention, the initiator used has a simple structure, which is beneficial for further promoting the trifluoromethylation reaction of olefins. Diethylhydroxylamine is a colorless and transparent liquid. This reagent is inexpensive and readily available, insensitive to water and oxygen, easy to store and use, readily soluble in water, and easily separated from the reaction system, which is beneficial for further and more efficiently promoting the trifluoromethylation reaction of olefins.
[0033] In some embodiments, the trifluoromethylating agent comprises at least one of the following structural formulas:
[0034]
[0035] Among them, OTf - Trifluoromethanesulfonic acid anion CF3SO3 - ;
[0036] Preferably, the trifluoromethylating agent comprises Togni reagent II:
[0037]
[0038] In this embodiment of the invention, a stable and easy-to-use trifluoromethylating reagent is used as a trifluoromethyl radical precursor to achieve trifluoromethylation of olefins.
[0039] In some embodiments, the olefin represented by formula (1) is a terminal olefin or an internal olefin; and / or, the olefin represented by formula (1) is an unactivated olefin or an activated olefin; preferably, R1, R2, and R3 in the olefin represented by formula (1) are each independently selected from hydrogen or non-hydrogen substituents; more preferably, R1 in the olefin represented by formula (1) is selected from alkyl, aryl, heteroaryl, ester, and amide groups; R2 is selected from hydrogen, alkyl, and aryl, optionally, the alkyl group is selected from methyl and ethyl, and the aryl group is selected from phenyl; R3 is selected from hydrogen and alkyl, optionally, the alkyl group is methyl. In the embodiments of the present invention, the trifluoromethylation method of the olefin of the present invention has wide applicability to olefins.
[0040] In some embodiments, the molar ratio of the olefin, the trifluoromethylating agent, and the hydroxylamine is 1-100:1-4:0.5-4, specifically, for example, 1:2.5:2, 5:4:4, 9:4:4, 10:4:4.
[0041] In some embodiments, the reaction also includes a base, wherein the olefin of formula (1), the trifluoromethylating agent, the hydroxylamine and the base are reacted in a solvent to obtain the trifluoromethylated product of the olefin of formula (2);
[0042]
[0043] Preferably, the base includes at least one of sodium carbonate, potassium carbonate, calcium carbonate, potassium fluoride, potassium bicarbonate, sodium bicarbonate, sodium monohydrogen phosphate, sodium dihydrogen phosphate, and calcium fluoride; more preferably, sodium carbonate. In this embodiment of the invention, without the addition of a base, the olefin shown in formula (1), the trifluoromethylating agent, and hydroxylamine can react to obtain the trifluoromethylated product of the olefin shown in formula (2). The addition of a base can promote the reaction because the base and hydroxylamine (e.g., diethylhydroxylamine) interact, increasing the electron-donating ability of hydroxylamine, promoting the single-electron transfer reaction between hydroxylamine and the trifluoromethylating agent, and the resulting trifluoromethyl radical adds to the olefin, thus increasing the reaction yield. The combination of hydroxylamine / base is selected as the initiator. The initiator has a simple structure, and the inorganic base is inexpensive and stable, avoiding the use of strong bases. Under mild conditions, non-transition metals promote the trifluoromethylation of olefins.
[0044] In some embodiments, the molar ratio of the olefin to the base is 1-100:0-4, optionally 1-100:0.1-4, specifically, for example, 1:2, 2:2, 5:4; the molar ratio of the olefin, trifluoromethylating agent, hydroxylamine and base is 1-100:1-4:0.5-4:0-4, specifically, for example, 1:2.5:2:2.
[0045] In some embodiments, the reaction temperature is 86-150°C, specifically, for example, 86°C, 90°C, 100°C, 110°C, 120°C, 130°C, 140°C, 150°C, preferably 150°C; and / or, the reaction time is 7-72 hours, specifically, for example, 7 hours, 12 hours, 24 hours, 48 hours, 60 hours, 72 hours. In the embodiments of the present invention, experimental studies have found that under low-temperature conditions (e.g., 60°C), the oxidative trifluoromethylation product of the olefin is the main product. However, as the reaction temperature increases, the proportion of the olefin trifluoromethylation product gradually increases. If the temperature continues to rise, for example, part of the reaction is heated to 150°C, only the olefin trifluoromethylation product is found during product characterization after the reaction. Wherein, when the hydroxylamine has the structural formula (R)₂NOH, the structural formula of the olefin oxidative trifluoromethylation product is as follows:
[0046]
[0047] In some embodiments, the reaction is carried out in an inert gas atmosphere, preferably argon.
[0048] In some embodiments, the reaction includes: performing a first-stage reaction at a first temperature, and then raising the temperature to a second temperature for a second-stage reaction to obtain the trifluoromethylated product of the olefin shown in formula (2); preferably, the temperature of the first-stage reaction is 60-85°C, specifically, for example, 60°C, 65°C, 70°C, 75°C, 80°C, 85°C; the reaction time of the first-stage reaction is 1-6 hours, specifically, for example, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours; the reaction temperature of the second-stage reaction is 140-170°C, specifically, for example, 140°C, 150°C, 160°C, 170°C; the reaction time of the second-stage reaction is 7-72 hours, specifically, for example, 7 hours, 12 hours, 24 hours, 48 hours, 60 hours, 72 hours. In the embodiments of the present invention, the reaction preferably includes two reaction stages, which can efficiently obtain the trifluoromethylated product of the olefin and further improve the yield.
[0049] In some embodiments, the solvent includes at least one selected from acetonitrile, tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, dimethyl sulfoxide, ethylene glycol dimethyl ether, and ethylene glycol monomethyl ether.
[0050] In some embodiments, the solvent is N,N-dimethylformamide.
[0051] In some embodiments, the solvent includes acetonitrile, tetrahydrofuran, and N,N-dimethylformamide, preferably, the volume ratio of acetonitrile, tetrahydrofuran, and N,N-dimethylformamide is 1:2:3.
[0052] In some embodiments, the solvent comprises acetonitrile and 1,4-dioxane, wherein the volume ratio of acetonitrile to 1,4-dioxane is 1-10:10-1, specifically, for example, 1:10, 1:5, 1:2, 1:1, 2:1, 5:1, 10:1.
[0053] In some embodiments, the first stage reaction is carried out in a first solvent.
[0054] In some embodiments, the first solvent comprises at least one of acetonitrile, tetrahydrofuran, and 1,4-dioxane; preferably, the first solvent comprises acetonitrile and tetrahydrofuran, wherein the volume ratio of acetonitrile to tetrahydrofuran is 1-10:10-1, specifically, for example, 1:10, 1:5, 1:2, 1:1, 2:1, 5:1, 10:1, preferably, 1:2; and / or, the first solvent comprises acetonitrile and 1,4-dioxane, wherein the volume ratio of acetonitrile to 1,4-dioxane is 1-10:10-1, specifically, for example, 1:10, 1:5, 1:2, 1:1, 2:1, 5:1, 10:1.
[0055] In some embodiments, a second solvent is added to the second stage reaction, preferably N,N-dimethylformamide.
[0056] In some embodiments, a first-stage reaction is carried out at a first temperature, cooled to room temperature, a second solvent is added, and then the temperature is raised to a second temperature to carry out a second-stage reaction.
[0057] In some embodiments, the first solvent comprises acetonitrile and tetrahydrofuran, wherein the volume ratio of acetonitrile to tetrahydrofuran is 1:2; the second solvent is N,N-dimethylformamide; the volume ratio of the first solvent to the second solvent is 1:1, that is, the volume ratio of acetonitrile, tetrahydrofuran and N,N-dimethylformamide is 1:2:3.
[0058] In some embodiments, the ratio of the amount of olefin to the volume of solvent is 0.1 mmol:0.1 mL to 0.1 mmol:10 mL, specifically, for example, 0.1 mmol:0.1 mL, 0.1 mmol:0.2 mL, 0.1 mmol:0.5 mL, 0.1 mmol:1 mL, 0.1 mmol:2 mL, 0.1 mmol:5 mL, 0.1 mmol:8 mL, 0.1 mmol:10 mL.
[0059] In some embodiments, in the first stage reaction, the ratio of the amount of olefin to the volume of solvent is 0.1 mmol:0.1 mL to 0.1 mmol:5 mL, specifically, for example, 0.1 mmol:0.1 mL, 0.1 mmol:0.2 mL, 0.1 mmol:0.5 mL, 0.1 mmol:1 mL, 0.1 mmol:2 mL, 0.1 mmol:5 mL; in the second stage reaction, the ratio of the amount of olefin to the volume of solvent is 0.1 mmol:0.2 mL to 0.1 mmol:10 mL, specifically, for example, 0.1 mmol:0.2 mL, 0.1 mmol:1 mL, 0.1 mmol:2 mL, 0.1 mmol:5 mL, 0.1 mmol:8 mL, 0.1 mmol:10 mL.
[0060] In some embodiments, the reaction product is washed with water, then the aqueous phase is extracted with dichloromethane, the organic solvent is dried, the solvent is evaporated, and the product is separated by silica gel column chromatography and / or thin-layer chromatography to obtain the trifluoromethylated product of the olefin shown in formula (2).
[0061] The present invention will now be described with reference to specific embodiments. It should be noted that these embodiments are merely descriptive and do not limit the present invention in any way. Specific implementation method one:
[0063] Togni reagent II (2.5 mmol) and Et₂NOH (2.0 mmol), along with an olefin (1.0 mmol), were prepared under an Ar atmosphere. A half-mixture of MeCN and THF (1 mL) was added to the reaction tube. The reaction was carried out at 80 °C for 2 hours. After cooling to room temperature, DMF (1 mL) was added, and the temperature was raised to 150 °C. The reaction was completed after approximately 24 hours. Trifluorotoluene was added as an internal standard, and the yield of the compound was characterized by fluorine chromatography, as shown below. Based on this, approximately 3 × 3 mL of deionized water was added to wash away the DMF, and the aqueous phase was extracted with dichloromethane. The organic solvent was dried over anhydrous sodium sulfate, evaporated to dryness, and the product was obtained by silica gel column chromatography and preparative thin-layer chromatography, as shown in Example 1.
[0064]
[0065] Example 1:
[0066]
[0067] The yield was 76%.
[0068] 1H NMR (400MHz, CDCl3) δ7.67(dd,J=7.9,4.4Hz,4H),7.54(dd,J=23.7,7.8Hz,4H),7.45(d,J=7.2Hz,1H),7.31-7.20(m,1H),6.29(dq,J=16.1,6.5Hz,1H).
[0069] 19 F NMR (376MHz, CDCl3) δ-63.12 (d, J=6.8Hz). Specific Implementation Method Two:
[0071] Synthesis of olefin trifluoromethylation products:
[0072] Sodium carbonate (0.2 mmol), trifluoromethylating agent Togni reagent II (0.25 mmol), Et₂NOH (0.2 mmol), and olefin (0.1 mmol) were reacted under an Ar atmosphere. After the reaction, approximately 3 × 3 mL of deionized water was added to wash away DMF, and the aqueous phase was extracted with dichloromethane. The organic solvent was dried over anhydrous sodium sulfate, evaporated to dryness, and separated by silica gel column chromatography to obtain the product. The yields are shown below and in Examples 2 and 3. The reactions described are as follows:
[0073] a React in DMF (1 mL) at 150 °C for 7-72 hours.
[0074] b Add 1 mL of a half-mixed solution of MeCN and THF to the reaction tube. After reacting at 80°C for 2 hours, cool to room temperature and add 1 mL of DMF. Then heat to 150°C and react for 7-72 hours.
[0075] c Add 1 mL of DMF to the reaction tube and react at 80 °C for 2 hours. Then, increase the temperature to 150 °C and react for 7-72 hours.
[0076]
[0077] Example 2:
[0078]
[0079] The yield was 96%.
[0080] 1H NMR (400MHz, CDCl3) δ7.67(dd,J=7.9,4.4Hz,4H),7.54(dd,J=23.7,7.8Hz,4H),7.45(d,J=7.2Hz,1H),7.31-7.20(m,1H),6.29(dq,J=16.1,6.5Hz,1H).
[0081] 19 F NMR (376MHz, CDCl3) δ-63.12 (d, J=6.8Hz).
[0082] Example 3:
[0083]
[0084] The yield was 98%.
[0085] 1 H NMR (400MHz, CDCl3) δ7.48-7.33 (m, 4H), 7.16 (t, J = 7.5Hz, 1H), 7.13-7.07 ( m,1H),7.07-7.01(m,2H),7.02-6.94(m,2H),6.10(dq,J=16.1,6.5Hz,1H).
[0086] 19 F NMR (376MHz, CDCl3) δ-63.02 (dd, J=6.8, 2.3Hz).
[0087] In this invention, the terms "one embodiment," "some embodiments," "example," "specific example," or "some examples," etc., refer to a specific feature, structure, material, or characteristic described in connection with that embodiment or example, which is included in at least one embodiment or example of the invention. In this specification, the illustrative expressions of the above terms do not necessarily refer to the same embodiment or example. Furthermore, the specific features, structures, materials, or characteristics described may be combined in any suitable manner in one or more embodiments or examples. Moreover, without contradiction, those skilled in the art can combine and integrate the different embodiments or examples described in this specification, as well as the features of different embodiments or examples.
[0088] Although the above embodiments have been shown and described, it is understood that the above embodiments are exemplary and should not be construed as limiting the present invention. Any changes, modifications, substitutions and variations made to the above embodiments by those skilled in the art are within the protection scope of the present invention.
Claims
1. A method for trifluoromethylation of olefins, characterized in that, include: The olefin shown in formula (1), the trifluoromethylating agent, and the hydroxylamine are reacted in a solvent to give the trifluoromethylated olefin shown in formula (2): ； In the olefin shown in formula (1), R1 is selected from alkyl, aryl, heteroaryl, ester, and amide groups; R2 is selected from hydrogen, alkyl, and aryl groups; and R3 is selected from hydrogen and alkyl groups. The hydroxylamine includes at least one of the following structural formulas: ； The trifluoromethylating agent includes at least one of the following structural formulas: 。 2. The method for trifluoromethylation of olefins according to claim 1, characterized in that, The olefins shown in formula (1) are terminal olefins or internal olefins; And / or, the olefin shown in formula (1) is an unactivated olefin or an activated olefin.
3. The method for trifluoromethylation of olefins according to claim 1, characterized in that, R2 and R3 in the olefin shown in formula (1) are each independently selected from hydrogen or non-hydrogen substituents.
4. The method for trifluoromethylation of olefins according to claim 1, characterized in that, It also includes a base, wherein the olefin shown in formula (1), the trifluoromethylating agent, the hydroxylamine and the base are reacted in a solvent to obtain the trifluoromethylated product of the olefin shown in formula (2); the base includes at least one of sodium carbonate, potassium carbonate, calcium carbonate, potassium fluoride, potassium bicarbonate, sodium bicarbonate, sodium monohydrogen phosphate, sodium dihydrogen phosphate and calcium fluoride.
5. The method for trifluoromethylation of olefins according to claim 1 or 4, characterized in that, The molar ratio of the olefin, the trifluoromethylating agent, and the hydroxylamine is 1-100:1-4:0.5-4; And / or, the molar ratio of the olefin to the base is 1-100:0-4.
6. The method for trifluoromethylation of olefins according to claim 1 or 4, characterized in that, The reaction temperature is 86-150 ℃; And / or, the reaction time is 7-72 h; And / or, the reaction is carried out in an inert gas atmosphere.
7. The method for trifluoromethylation of olefins according to claim 1 or 4, characterized in that, The reaction includes: carrying out a first-stage reaction at a first temperature, and then raising the temperature to a second temperature to carry out a second-stage reaction, to obtain the trifluoromethylated product of the olefin shown in formula (2).
8. The method for trifluoromethylation of olefins according to claim 7, characterized in that, The temperature of the first stage reaction is 60-85℃; the reaction time of the first stage reaction is 1-6h; the temperature of the second stage reaction is 140-170℃; the reaction time of the second stage reaction is 7-72h.
9. The method for trifluoromethylation of olefins according to claim 1 or 4, characterized in that, The solvent includes at least one of acetonitrile, tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, dimethyl sulfoxide, ethylene glycol dimethyl ether, and ethylene glycol monomethyl ether.