Copper-catalyzed regioselective olefination and trifluoromethylation of carboxylic acids to produce (Z)-trifluoromethane enol esters

Abstract

The present invention aims to provide a method for generating (Z)-trifluoromethane enol esters by regioselective olefination and trifluoromethylation of a copper-catalyzed carboxylic acid. The reaction shows tolerance to various unactivated carboxylic acids, and the corresponding regioselectivity and stereoselectivity product yields are high, and the reaction conditions are mild. The catalytic scheme has the advantages of a wide range of raw materials, no noble metals and noxious byproducts. This strategy for synthesizing (Z)-vinyl trifluoromethane esters can open a door for highly functionalized or complex olefins, which are still difficult to prepare using traditional synthetic methods.

Description

[Technical field]

[0001] The present invention relates to the first example of synthesizing (Z)-α-substituted trifluoromethyl enol esters by copper-catalyzed olefination and trifluoromethylation of unactivated carboxylic acids with (trifluoromethyl)trimethylsilane (TMSCF3). The esters contain both olefin trifluoromethyl and enol ester units. By using an inexpensive CuCl catalyst, the scheme does not require complex ligands and sensitive organometallic reagents. The method exhibits impressive functional group tolerance and substrate scope, with excellent chemical selectivity, regioselectivity and stereoselectivity. It achieves the construction of multi-substituted olefin compounds with high regioselectivity and stereoselectivity from unactivated carboxylic acids without deacidification, and for the first time completes the challenge of constructing olefin trifluoromethyl ester compounds only from carboxylic acids. [Background technology]

[0002] Enol esters are important synthetic raw materials and the basis for the preparation of plasticizers, drugs, bioactive molecules and fluorescent materials. At the same time, in the transformation process of organic synthesis, the enol ester structure has always played an irreplaceable core component, such as the famous Diels-Alder reaction, asymmetric hydrogenation, olefin metathesis and Mizoroki-Heck reaction. Among the various synthetic methods of enol esters, the transformation of organic acids is one of the most ideal methods. The main reason is that they can be obtained by enzyme catalysis, microbial fermentation and isolation from plants in nature. At the same time, it is also a way to convert renewable resources into high-value-added chemicals, providing a potential sustainable solution to the growing global demand for chemicals and fuels. At present, the method of catalytically generating enol esters by adding carboxylic acids to alkynes is one of the recognized and most reliable strategies. Although these known methods have undeniable scientific contributions and comprehensive benefits. However, designing methods to obtain structurally diverse enol esters only from readily available carboxylic acids remains an important synthetic challenge that has not been solved. The regioselectivity and stereoselectivity of the synthesis of trisubstituted and tetrasubstituted functional enol esters starting from carbonyl acids remain difficult to control. Therefore, it would be an interesting topic to construct multi-substituted enol esters from two carboxylic acid molecules with good chemo-, regio-, and stereoselectivity.

[0003] At the same time, due to its unique chemical and physical properties (high lipid solubility, metabolic stability, antioxidant activity), trifluoromethyl enol esters are widely used in the fields of medicine, pesticides, fine chemicals and materials. At present, among the known synthesis methods of trifluoromethyl enol esters, the trifluoromethylation reaction of carboxylic acid and alkyne is the main route to synthesize this compound. However, the direct conversion of cheap and abundant carboxylic acids into trifluoromethyl enol esters is not clear in the literature, and it is impossible to synthesize α-substituted trifluoromethyl enol esters by the addition of carboxylic acid and alkyne. Therefore, another goal of this study is to develop a feasible catalytic method to meet this unknown challenge. At present, there are no public documents and patent applications for the synthesis of (Z)-α-substituted trifluoromethyl enol ester compounds at home and abroad. [Summary of the invention]

[0004] The present invention develops an efficient transformation method of (Z)-vinyl trifluoromethane ester scaffold using inexpensive copper as catalyst. The reaction shows tolerance to various unactivated carboxylic acids, corresponding high regio- and stereo-selective product yields, and mild reaction conditions. The catalytic scheme has the advantages of a wide range of raw materials, no noble metals and no harmful byproducts. This strategy for the synthesis of (Z)-vinyl trifluoromethane esters can open a door to highly functionalized or complex olefins, which are still difficult to prepare using traditional synthetic methods.

[0005]

[0006] Wherein R 3 is an aromatic group (phenyl, etc.), R 4 It is an alkane group (methyl, etc.).

Brief Description of the Drawings

[0007] Attached Figure 1 The following is a synthetic route for (Z)-α-substituted trifluoromethyl enol ester derivatives. Figure 2 Shown is a scheme for the transformation of (Z)-α-substituted trifluoromethyl enol esters. [Specific implementation method]

[0008]

[0009] Wherein R 1 is a benzene ring substituent (methyl, methoxy, chlorine, etc.); R 2 Alkane group (methyl)

[0010] Example 1:

[0011] Phenylacetic acid (0.30mmol, 1.0 equivalent), CuCl (0.03 mmol, 0.1 equivalent) and NaI (0.69mmol, 2.3 equivalent) were added to a 10mL Schlenk tube equipped with magnetic stirring. After vacuuming with a pump, nitrogen was filled three times. Then, 1.0mL of ultra-dry solvent tetrahydrofuran and TMSCF3 (0.6mmol, 2.0 equivalent) were added under N2 atmosphere. The mixture was stirred at 70°C for 12 hours (constant temperature oil bath). After cooling to room temperature, the mixture was diluted with ethyl acetate, and then an appropriate amount of water was added, and then extracted with ethyl acetate three times, the organic phase was collected, and an appropriate amount of anhydrous Na2SO4 was added to dehydrate the combined organic layer, and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel to obtain a trifluoromethyl enol ester derivative substituted with (Z)-α-position.

[0012] The title compound was obtained by column chromatography (petroleum ether / ethyl acetate = 100:1) as a yellow oil. Yield: 36.7 mg, 80%. 1 H NMR (400MHz, CDCl3) δ7.40-7.17(m,10H),6.84(s,1H),3.81(s,2H). 13 C NMR (101MHz, CDCl3) δ167.3,134.4,134.0,132.1,130.7,129.6,129.5,129.1,128.9,128.7, 127.7,123.4,123.4,121.6,118.9,41.0. 19 F NMR(377MHz,CDCl3)δ-70.12.HRMS(ESI)m / z: [M + H] + Calculate for C 17 H 14 F3O2 + Found 307.0946.

[0013] Example 2:

[0014] Methoxyphenylacetic acid (methoxy position = para, meta, ortho) (0.30mmol, 1.0 equivalent), CuCl (0.03mmol, 0.1 equivalent) and NaI (0.69mmol, 2.3 equivalent) were added to a 10mL Schlenk tube equipped with magnetic stirring. After vacuuming with a pump, nitrogen was filled three times. Then, 1.0mL of ultra-dry solvent tetrahydrofuran and TMSCF3 (0.6mmol, 2.0 equivalent) were added under N2 atmosphere. The mixture was stirred at 70°C for 12 hours (constant temperature oil bath). After cooling to room temperature, the mixture was diluted with ethyl acetate, and then an appropriate amount of water was added, and then extracted with ethyl acetate three times, the organic phase was collected, and an appropriate amount of anhydrous Na2SO4 was added to dehydrate the combined organic layer, and concentrated under reduced pressure. The crude product was separated by column chromatography on silica gel to obtain purified (Z)-α-substituted trifluoromethyl enol ester derivatives.

[0015] Example 3:

[0016] Bromophenylacetic acid (bromine position = para, meta, ortho) (0.30mmol, 1.0 equivalent), CuCl (0.03mmol, 0.1 equivalent) and NaI (0.69mmol, 2.3 equivalent) were added to a 10mL Schlenk tube equipped with magnetic stirring. After vacuuming with a pump, nitrogen was filled three times. Then, 1.0mL of ultra-dry solvent tetrahydrofuran and TMSCF3 (0.6mmol, 2.0 equivalent) were added under N2 atmosphere. The mixture was stirred at 70°C for 12 hours (constant temperature oil bath). After cooling to room temperature, the mixture was diluted with ethyl acetate, and then an appropriate amount of water was added, and then extracted with ethyl acetate three times, the organic phase was collected, and an appropriate amount of anhydrous Na2SO4 was added to dehydrate the combined organic layer, and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel to obtain a trifluoromethyl enol ester derivative substituted with the (Z)-α-position.

[0017] Example 4:

[0018] Tolueneacetic acid (methyl position = para, meta, ortho) (0.30mmol, 1.0 equivalent), CuCl (0.03mmol, 0.1 equivalent) and NaI (0.69mmol, 2.3 equivalent) were added to a 10mL Schlenk tube equipped with magnetic stirring. After vacuuming with a pump, nitrogen was filled three times. Then, 1.0mL of ultra-dry solvent tetrahydrofuran and TMSCF3 (0.6mmol, 2.0 equivalent) were added under N2 atmosphere. The mixture was stirred at 70°C for 12 hours (constant temperature oil bath). After cooling to room temperature, the mixture was diluted with ethyl acetate, and then an appropriate amount of water was added, and then extracted with ethyl acetate three times, the organic phase was collected, and an appropriate amount of anhydrous Na2SO4 was added to dehydrate the combined organic layer, and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel to obtain a trifluoromethyl enol ester derivative substituted with the (Z)-α-position.

[0019] Example 5:

[0020] Halogen-substituted phenylacetic acid (halogen = fluorine, chlorine, iodine) (0.30 mmol, 1.0 equivalent), CuCl (0.03 mmol, 0.1 equivalent) and NaI (0.69 mmol, 2.3 equivalent) were added to a 10 mL Schlenk tube equipped with magnetic stirring. After vacuuming with a pump, nitrogen was filled three times. Then, 1.0 mL of ultra-dry solvent tetrahydrofuran and TMSCF3 (0.6 mmol, 2.0 equivalent) were added under N2 atmosphere. The mixture was stirred at 70°C for 12 hours (constant temperature oil bath). After cooling to room temperature, the mixture was diluted with ethyl acetate, an appropriate amount of water was added, and then extracted three times with ethyl acetate, the organic phase was collected, and an appropriate amount of anhydrous Na2SO4 was added to dehydrate the combined organic layer, and concentrated under reduced pressure. The crude product was separated by column chromatography on silica gel to obtain purified (Z)-α-substituted trifluoromethyl enol ester derivatives.

[0021] Example 6:

[0022] 3,4,5-methoxyphenylacetic acid (0.30mmol, 1.0 equivalent), CuCl (0.03mmol, 0.1 equivalent) and NaI (0.69mmol, 2.3 equivalent) were added to a 10mL Schlenk tube equipped with magnetic stirring. After vacuuming with a pump, nitrogen was filled three times. Then, 1.0mL of ultra-dry solvent tetrahydrofuran and TMSCF3 (0.6mmol, 2.0 equivalent) were added under N2 atmosphere. The mixture was stirred at 70°C for 12 hours (constant temperature oil bath). After cooling to room temperature, the mixture was diluted with ethyl acetate, and then an appropriate amount of water was added, and then extracted with ethyl acetate three times, the organic phase was collected, and an appropriate amount of anhydrous Na2SO4 was added to dehydrate the combined organic layer, and concentrated under reduced pressure. The crude product was separated by column chromatography on silica gel to obtain purified (Z)-α-substituted trifluoromethyl enol ester derivatives.

[0023] Example 7:

[0024] 4-phenoxy-phenylacetic acid (0.30mmol, 1.0 equivalent), CuCl (0.03mmol, 0.1 equivalent) and NaI (0.69mmol, 2.3 equivalent) are added to the 10mL Schlenk tube equipped with magnetic stirring. Fill nitrogen with pump vacuumization, three times. Then, add 1.0mL ultra-dry solvent tetrahydrofuran and TMSCF3 (0.6mmol, 2.0 equivalent) under N2 atmosphere. The mixture was stirred for 12 hours at 70 ℃ (constant temperature oil bath). After cooling to room temperature, the mixture was diluted with ethyl acetate, and then an appropriate amount of water was added, and then extracted with ethyl acetate three times, and organic phase was collected, and an appropriate amount of anhydrous Na2SO4 was added to dehydrate the combined organic layer, and concentrated under reduced pressure. The crude product was purified by column chromatography separation method on silica gel to obtain the trifluoromethyl enol ester derivatives substituted by the (Z)-α-position.

[0025] Example 8:

[0026] 2-thiophenephenylacetic acid (0.30mmol, 1.0 equivalent), CuCl (0.03mmol, 0.1 equivalent) and NaI (0.69mmol, 2.3 equivalent) were added to the 10mL Schlenk tube equipped with magnetic stirring. Nitrogen was filled after vacuuming with a pump for three times. Then, 1.0mL of ultra-dry solvent tetrahydrofuran and TMSCF (0.6mmol, 2.0 equivalent) were added under N2 atmosphere. The mixture was stirred for 12 hours at 70 ℃ (constant temperature oil bath). After cooling to room temperature, the mixture was diluted with ethyl acetate, and then an appropriate amount of water was added, and then extracted with ethyl acetate three times, and the organic phase was collected, and an appropriate amount of anhydrous Na2SO4 was added to dehydrate the combined organic layer, and concentrated under reduced pressure. The crude product was purified by column chromatography separation method on silica gel to obtain the trifluoromethyl enol ester derivatives substituted with the (Z)-α-position.

[0027] Example 9:

[0028] 2-naphthylphenylacetic acid (0.30mmol, 1.0 equivalent), CuCl (0.03mmol, 0.1 equivalent) and NaI (0.69mmol, 2.3 equivalent) were added to the 10mL Schlenk tube equipped with magnetic stirring. Nitrogen was filled after vacuuming with a pump for three times. Then, 1.0mL of ultra-dry solvent tetrahydrofuran and TMSCF (0.6mmol, 2.0 equivalent) were added under N2 atmosphere. The mixture was stirred for 12 hours at 70 ℃ (constant temperature oil bath). After cooling to room temperature, the mixture was diluted with ethyl acetate, and then an appropriate amount of water was added, and then extracted with ethyl acetate three times, the organic phase was collected, and an appropriate amount of anhydrous Na2SO4 was added to dehydrate the combined organic layer, and concentrated under reduced pressure. The crude product was purified by column chromatography separation method on silica gel to obtain the trifluoromethyl enol ester derivatives substituted with the (Z)-α-position.

[0029] Example 10:

[0030] 2-(2,3-dihydrobenzofuran-6-yl)acetic acid (0.30mmol, 1.0 equivalent), CuI (0.03mmol, 0.1 equivalent) and sodium iodide (NaI, 0.60mmol, 2.0 equivalent) were added to a 10mL Schlenk tube equipped with a magnetic stirrer. After vacuuming with a pump, nitrogen was filled three times. Then, 1.0mL of ultra-dry solvent tetrahydrofuran, trifluoromethyltrimethylsilane TMSCF3, (0.6mmol, 2.0 equivalent), and deionized water (0.45mmol, 1.5 equivalent) were added under N2 atmosphere. The mixture was stirred at 150°C for 12 hours (constant temperature oil bath). After cooling to room temperature, the mixture was diluted with ethyl acetate, an appropriate amount of water was added, and then extracted three times with ethyl acetate, the organic phase was collected, and an appropriate amount of anhydrous Na2SO4 was added to dehydrate the combined organic layer, and concentrated under reduced pressure. The crude product was separated by column chromatography on silica gel to obtain purified (Z)-α-substituted trifluoromethyl enol ester derivatives.

[0031] Example 11:

[0032] Phenylpropionic acid (0.30mmol, 1.0 equivalent), CuI (0.03mmol, 0.1 equivalent) and sodium iodide (NaI, 0.60mmol, 2.0 equivalent) were added to a 10mL Schlenk tube equipped with magnetic stirring. Nitrogen was filled after vacuuming with a pump for three times. Then, 1.0mL of ultra-dry solvent tetrahydrofuran, trifluoromethyltrimethylsilane (TMSCF3, 0.6mmol, 2.0 equivalent), and deionized water (0.45mmol, 1.5 equivalent) were added under N2 atmosphere. The mixture was stirred for 12 hours at 150°C (constant temperature oil bath). After cooling to room temperature, the mixture was diluted with ethyl acetate, and then an appropriate amount of water was added, and then extracted with ethyl acetate three times, the organic phase was collected, and an appropriate amount of anhydrous Na2SO4 was added to dehydrate the combined organic layer, and concentrated under reduced pressure. The crude product was purified by column chromatography separation method on silica gel to obtain the trifluoromethyl enol ester derivatives substituted with the (Z)-α-position.

[0033] Example 12:

[0034] Add phenylbutyric acid (0.30mmol, 1.0 equivalent), CuI (0.03mmol, 0.1 equivalent) and sodium iodide (NaI, 0.60mmol, 2.0 equivalent) to a 10mL Schlenk tube equipped with magnetic stirring. Fill with nitrogen after vacuuming with a pump, three times. Then, add 1.0mL of ultra-dry solvent tetrahydrofuran, trifluoromethyltrimethylsilane (TMSCF3, 0.6mmol, 2.0 equivalent), deionized water (0.45mmol, 1.5 equivalent) under N2 atmosphere. The mixture is stirred at 150°C for 12 hours (constant temperature oil bath). After cooling to room temperature, the mixture is diluted with ethyl acetate, and then an appropriate amount of water is added, and then extracted with ethyl acetate three times, the organic phase is collected, and an appropriate amount of anhydrous Na2SO4 is added to dehydrate the combined organic layer, and concentrated under reduced pressure. The crude product is purified by column chromatography separation method on silica gel to obtain a trifluoromethyl enol ester derivative substituted with (Z)-α-position.

[0035] Example 13:

[0036] Indomethacin (0.30mmol, 1.0 equivalent), CuI (0.03 mmol, 0.1 equivalent) and sodium iodide (NaI, 0.60mmol, 2.0 equivalent) were added to a 10mL Schlenk tube equipped with magnetic stirring. After vacuuming with a pump, nitrogen was filled three times. Then, 1.0mL of ultra-dry solvent tetrahydrofuran, trifluoromethyltrimethylsilane (TMSCF3, 0.6mmol, 2.0 equivalent), and deionized water (0.45mmol, 1.5 equivalent) were added under N2 atmosphere. The mixture was stirred at 150°C for 12 hours (constant temperature oil bath). After cooling to room temperature, the mixture was diluted with ethyl acetate, and then an appropriate amount of water was added, and then extracted with ethyl acetate three times, the organic phase was collected, and an appropriate amount of anhydrous Na2SO4 was added to dehydrate the combined organic layer, and concentrated under reduced pressure. The crude product was separated by column chromatography on silica gel to obtain purified (Z)-α-substituted trifluoromethyl enol ester derivatives.

[0037] Example 14:

[0038] Add isoxic acid (0.30mmol, 1.0 equivalent), CuI (0.03 mmol, 0.1 equivalent) and sodium iodide (NaI, 0.60mmol, 2.0 equivalent) to a 10mL Schlenk tube equipped with magnetic stirring. Fill with nitrogen after vacuuming with a pump, three times. Then, add 1.0mL of ultra-dry solvent tetrahydrofuran, trifluoromethyltrimethylsilane (TMSCF3, 0.6mmol, 2.0 equivalent), and deionized water (0.45mmol, 1.5 equivalent) under N2 atmosphere. The mixture is stirred at 150°C for 12 hours (constant temperature oil bath). After cooling to room temperature, the mixture is diluted with ethyl acetate, and then an appropriate amount of water is added, and then extracted with ethyl acetate three times, the organic phase is collected, and an appropriate amount of anhydrous Na2SO4 is added to dehydrate the combined organic layer, and concentrated under reduced pressure. The crude product is separated by column chromatography on silica gel to obtain purified (Z)-α-substituted trifluoromethyl enol ester derivatives.

[0039] Example 15:

[0040] Phenoxyacetic acid (0.30mmol, 1.0 equivalent), CuI (0.03 mmol, 0.1 equivalent) and sodium iodide (NaI, 0.60mmol, 2.0 equivalent) were added to a 10mL Schlenk tube equipped with magnetic stirring. After vacuuming with a pump, nitrogen was filled three times. Then, 1.0mL of ultra-dry solvent tetrahydrofuran, trifluoromethyltrimethylsilane (TMSCF3, 0.6mmol, 2.0 equivalent), and deionized water (0.45mmol, 1.5 equivalent) were added under N2 atmosphere. The mixture was stirred at 150°C for 12 hours (constant temperature oil bath). After cooling to room temperature, the mixture was diluted with ethyl acetate, and then an appropriate amount of water was added, and then extracted with ethyl acetate three times, the organic phase was collected, and an appropriate amount of anhydrous Na2SO4 was added to dehydrate the combined organic layer, and concentrated under reduced pressure. The crude product was separated by column chromatography on silica gel to obtain purified (Z)-α-substituted trifluoromethyl enol ester derivatives.

[0041] Example 16:

[0042] Halogen-substituted phenoxyacetic acid (halogen = fluorine, bromine, iodine) (0.30 mmol, 1.0 equivalent), CuI (0.03mmol, 0.1 equivalent) and sodium iodide (NaI, 0.60mmol, 2.0 equivalent) were added to a 10mL Schlenk tube equipped with a magnetic stirrer. After vacuuming with a pump, nitrogen was filled three times. Then, 1.0mL of ultra-dry solvent tetrahydrofuran, trifluoromethyltrimethylsilane (TMSCF3, 0.6mmol, 2.0 equivalent), and deionized water (0.45mmol, 1.5 equivalent) were added under N2 atmosphere. The mixture was stirred at 150°C for 12 hours (constant temperature oil bath). After cooling to room temperature, the mixture was diluted with ethyl acetate, and then an appropriate amount of water was added, and then extracted with ethyl acetate three times, the organic phase was collected, and an appropriate amount of anhydrous Na2SO4 was added to dehydrate the combined organic layer, and concentrated under reduced pressure. The crude product was separated by column chromatography on silica gel to obtain purified (Z)-α-substituted trifluoromethyl enol ester derivatives.

[0043] Example 17:

[0044] Chloro-substituted phenoxyacetic acid (chloro position = para, meta) (0.30 mmol, 1.0 equivalent), CuI (0.03mmol, 0.1 equivalent) and sodium iodide (NaI, 0.60mmol, 2.0 equivalent) were added to a 10mL Schlenk tube equipped with a magnetic stirrer. After vacuuming with a pump, nitrogen was filled three times. Then, 1.0mL of ultra-dry solvent tetrahydrofuran, trifluoromethyltrimethylsilane (TMSCF3, 0.6mmol, 2.0 equivalent), and deionized water (0.45mmol, 1.5 equivalent) were added under N2 atmosphere. The mixture was stirred at 150°C for 12 hours (constant temperature oil bath). After cooling to room temperature, the mixture was diluted with ethyl acetate, and then an appropriate amount of water was added, and then extracted three times with ethyl acetate, the organic phase was collected, and an appropriate amount of anhydrous Na2SO4 was added to dehydrate the combined organic layer, and concentrated under reduced pressure. The crude product was separated by column chromatography on silica gel to obtain purified (Z)-α-substituted trifluoromethyl enol ester derivatives.

[0045] Example 18:

[0046] Methyl substituted phenoxyacetic acid (methyl position = para, meta, ortho) (0.30mmol, 1.0 equivalent), CuI (0.03mmol, 0.1 equivalent) and sodium iodide (NaI, 0.60mmol, 2.0 equivalent) were added to a 10mL Schlenk tube equipped with magnetic stirring. After vacuuming with a pump, nitrogen was filled three times. Then, 1.0mL of ultra-dry solvent tetrahydrofuran, trifluoromethyltrimethylsilane (TMSCF3, 0.6mmol, 2.0 equivalents), and deionized water (0.45mmol, 1.5 equivalents) were added under N2 atmosphere. The mixture was stirred at 150°C for 12 hours (constant temperature oil bath). After cooling to room temperature, the mixture was diluted with ethyl acetate, and then an appropriate amount of water was added, and then extracted with ethyl acetate three times, the organic phase was collected, and an appropriate amount of anhydrous Na2SO4 was added to dehydrate the combined organic layer, and concentrated under reduced pressure. The crude product was separated by column chromatography on silica gel to obtain purified (Z)-α-substituted trifluoromethyl enol ester derivatives.

[0047] Example 19:

[0048] 4-tert-butylphenoxyacetic acid or 4-isopropylphenylacetic acid (0.30 mmol, 1.0 equivalent), CuI (0.03mmol, 0.1 equivalent) and sodium iodide (NaI, 0.60mmol, 2.0 equivalent) were added to a 10mL Schlenk tube equipped with magnetic stirring. After vacuuming with a pump, nitrogen was filled three times. Then, 1.0mL of ultra-dry solvent tetrahydrofuran, trifluoromethyltrimethylsilane (TMSCF3, 0.6mmol, 2.0 equivalent), and deionized water (0.45mmol, 1.5 equivalent) were added under N2 atmosphere. The mixture was stirred at 150°C for 12 hours (constant temperature oil bath). After cooling to room temperature, the mixture was diluted with ethyl acetate, and then an appropriate amount of water was added, and then extracted with ethyl acetate three times, the organic phase was collected, and an appropriate amount of anhydrous Na2SO4 was added to dehydrate the combined organic layer, and concentrated under reduced pressure. The crude product was separated by column chromatography on silica gel to obtain purified (Z)-α-substituted trifluoromethyl enol ester derivatives.

[0049] Example 20:

[0050] 2-6-dimethyl-phenoxyacetic acid (0.30mmol, 1.0 equivalent), CuI (0.03mmol, 0.1 equivalent) and sodium iodide (NaI, 0.60mmol, 2.0 equivalent) were added to a 10mL Schlenk tube equipped with magnetic stirring. Nitrogen was filled after vacuuming with a pump, three times. Then, 1.0mL of ultra-dry solvent tetrahydrofuran, trifluoromethyltrimethylsilane (TMSCF3, 0.6mmol, 2.0 equivalent), and deionized water (0.45mmol, 1.5 equivalent) were added under N2 atmosphere. The mixture was stirred at 150°C for 12 hours (constant temperature oil bath). After cooling to room temperature, the mixture was diluted with ethyl acetate, and then an appropriate amount of water was added, and then extracted with ethyl acetate three times, the organic phase was collected, and an appropriate amount of anhydrous Na2SO4 was added to dehydrate the combined organic layer, and concentrated under reduced pressure. The crude product was separated by column chromatography on silica gel to obtain purified (Z)-α-substituted trifluoromethyl enol ester derivatives.

[0051] Example 21:

[0052] Methoxy-substituted phenoxyacetic acid (methoxy position = para, meta, ortho) (0.30mmol, 1.0 equivalent), CuI (0.03mmol, 0.1 equivalent) and sodium iodide (NaI, 0.60mmol, 2.0 equivalent) were added to a 10mL Schlenk tube equipped with magnetic stirring. After vacuuming with a pump, nitrogen was filled three times. Then, 1.0mL of ultra-dry solvent tetrahydrofuran, trifluoromethyltrimethylsilane (TMSCF3, 0.6mmol, 2.0 equivalents), and deionized water (0.45mmol, 1.5 equivalents) were added under N2 atmosphere. The mixture was stirred at 150°C for 12 hours (constant temperature oil bath). After cooling to room temperature, the mixture was diluted with ethyl acetate, and then an appropriate amount of water was added, and then extracted with ethyl acetate three times, the organic phase was collected, and an appropriate amount of anhydrous Na2SO4 was added to dehydrate the combined organic layer, and concentrated under reduced pressure. The crude product was separated by column chromatography on silica gel to obtain purified (Z)-α-substituted trifluoromethyl enol ester derivatives.

[0053] Example 22:

[0054] 2-3-dimethoxy-phenoxyacetic acid (0.30mmol, 1.0 equivalent), CuI (0.03mmol, 0.1 equivalent) and sodium iodide (NaI, 0.60mmol, 2.0 equivalent) were added to a 10mL Schlenk tube equipped with magnetic stirring. After vacuuming with a pump, nitrogen was filled three times. Then, 1.0mL of ultra-dry solvent tetrahydrofuran, trifluoromethyltrimethylsilane (TMSCF3, 0.6mmol, 2.0 equivalent), and deionized water (0.45mmol, 1.5 equivalent) were added under N2 atmosphere. The mixture was stirred at 150°C for 12 hours (constant temperature oil bath). After cooling to room temperature, the mixture was diluted with ethyl acetate, and then an appropriate amount of water was added, and then extracted with ethyl acetate three times, the organic phase was collected, and an appropriate amount of anhydrous Na2SO4 was added to dehydrate the combined organic layer, and concentrated under reduced pressure. The crude product was separated by column chromatography on silica gel to obtain purified (Z)-α-substituted trifluoromethyl enol ester derivatives.

[0055] Example 23:

[0056] 4-trifluoromethoxyphenoxyacetic acid (0.30mmol, 1.0 equivalent), CuI (0.03mmol, 0.1 equivalent) and sodium iodide (NaI, 0.60mmol, 2.0 equivalent) were added to a 10mL Schlenk tube equipped with magnetic stirring. After vacuuming with a pump, nitrogen was filled three times. Then, 1.0mL of ultra-dry solvent tetrahydrofuran, trifluoromethyltrimethylsilane (TMSCF3, 0.6mmol, 2.0 equivalents), and deionized water (0.45mmol, 1.5 equivalents) were added under N2 atmosphere. The mixture was stirred at 150°C for 12 hours (constant temperature oil bath). After cooling to room temperature, the mixture was diluted with ethyl acetate, and then an appropriate amount of water was added, and then extracted three times with ethyl acetate, the organic phase was collected, and an appropriate amount of anhydrous Na2SO4 was added to dehydrate the combined organic layer, and concentrated under reduced pressure. The crude product was separated by column chromatography on silica gel to obtain purified (Z)-α-substituted trifluoromethyl enol ester derivatives.

[0057] Example 24:

[0058] Add 1-naphthyloxyacetic acid or 2-naphthyloxyacetic acid (0.30mmol, 1.0 equivalent), CuI (0.03mmol, 0.1 equivalent) and sodium iodide (NaI, 0.60mmol, 2.0 equivalent) to the 10mL Schlenk tube equipped with magnetic stirring. Fill nitrogen with pump vacuumization, three times. Then, under N2 atmosphere, add 1.0mL ultra-dry solvent tetrahydrofuran, trifluoromethyltrimethylsilane (TMSCF3, 0.75mmol, 2.5 equivalent), deionized water (0.45mmol, 1.5 equivalent). The mixture was stirred at 150 ℃ for 12 hours (constant temperature oil bath). After cooling to room temperature, the mixture was diluted with ethyl acetate, added appropriate amount of water, extracted with ethyl acetate three times, collected organic phase, and added appropriate amount of anhydrous Na2SO4 dehydrated the combined organic layer, concentrated under reduced pressure. The crude product was separated by column chromatography on silica gel to obtain purified (Z)-α-substituted trifluoromethyl enol ester derivatives.

[0059] Example 25:

[0060] Add phenylthioacetic acid (0.30mmol, 1.0 equivalent), CuI (0.03 mmol, 0.1 equivalent) and sodium iodide (NaI, 0.60mmol, 2.0 equivalent) to a 10mL Schlenk tube equipped with magnetic stirring. Fill with nitrogen after vacuuming with a pump three times. Then, add 1.0mL of ultra-dry solvent tetrahydrofuran, trifluoromethyltrimethylsilane (TMSCF3, 0.6mmol, 2.0 equivalent), and deionized water (0.45mmol, 1.5 equivalent) under N2 atmosphere. The mixture is stirred at 150°C for 12 hours (constant temperature oil bath). After cooling to room temperature, the mixture is diluted with ethyl acetate, and then an appropriate amount of water is added, and then extracted with ethyl acetate three times, the organic phase is collected, and an appropriate amount of anhydrous Na2SO4 is added to dehydrate the combined organic layer, and concentrated under reduced pressure. The crude product is separated by column chromatography on silica gel to obtain purified (Z)-α-substituted trifluoromethyl enol ester derivatives.

[0061] Example 26:

[0062] 2-phenylpropionic acid (0.30mmol, 1.0 equivalent), CuI (0.03 mmol, 0.1 equivalent) and sodium iodide (NaI, 0.60mmol, 2.0 equivalent) were added to a 10mL Schlenk tube equipped with magnetic stirring. After vacuuming with a pump, nitrogen was filled three times. Then, 1.0mL of ultra-dry solvent tetrahydrofuran, trifluoromethyltrimethylsilane (TMSCF3, 0.6mmol, 2.0 equivalent), and deionized water (0.45mmol, 1.5 equivalent) were added under N2 atmosphere. The mixture was stirred at 150°C for 12 hours (constant temperature oil bath). After cooling to room temperature, the mixture was diluted with ethyl acetate, and then an appropriate amount of water was added, and then extracted with ethyl acetate three times, the organic phase was collected, and an appropriate amount of anhydrous Na2SO4 was added to dehydrate the combined organic layer, and concentrated under reduced pressure. The crude product was separated by column chromatography on silica gel to obtain purified (Z)-α-substituted trifluoromethyl enol ester derivatives.

[0063] Example 27:

[0064] Add meta-chloro-2-phenylpropionic acid (0.30mmol, 1.0 equivalent), CuI (0.03mmol, 0.1 equivalent) and sodium iodide (NaI, 0.60mmol, 2.0 equivalent) to a 10mL Schlenk tube equipped with magnetic stirring. Fill with nitrogen after vacuuming with a pump, three times. Then, add 1.0mL of ultra-dry solvent tetrahydrofuran, trifluoromethyltrimethylsilane (TMSCF3, 0.6mmol, 2.0 equivalent), deionized water (0.45mmol, 1.5 equivalent) under N2 atmosphere. The mixture is stirred at 150°C for 12 hours (constant temperature oil bath). After cooling to room temperature, the mixture is diluted with ethyl acetate, and then appropriate water is added, and then extracted with ethyl acetate three times, the organic phase is collected, and an appropriate amount of anhydrous Na2SO4 is added to dehydrate the combined organic layer, and concentrated under reduced pressure. The crude product was separated by column chromatography on silica gel to obtain purified (Z)-α-substituted trifluoromethyl enol ester derivatives.

[0065] Example 28:

[0066] (Z)-3,3,3-trifluoro-1-phenylprop-1-ene-2-yl 2-phenylacetate (0.30mmol, 1.0 equivalent) and KOH (0.6mmol, 2.0 equivalent) were added to a 10mL Schlenk tube equipped with a magnetic stirrer. After vacuuming with a pump, nitrogen was filled three times. Then, 1.0mL of ethanol was added under a N2 atmosphere. The mixture was refluxed and stirred for 12 hours (constant temperature oil bath). After cooling to room temperature, the mixture was diluted with ethyl acetate, an appropriate amount of water was added, and then extracted three times with ethyl acetate, the organic phase was collected, and an appropriate amount of anhydrous Na2SO4 was added to dehydrate the combined organic layers, and concentrated under reduced pressure. The crude product was separated by column chromatography on silica gel to obtain purified 1,1,1-trifluoro-3-phenylpropan-2-one.

[0067] Example 29:

[0068] Add (Z)-3,3,3-trifluoro-1-phenylprop-1-en-2-yl 2-phenylacetate (0.30mmol, 1.0 equivalent), ferrous chloride (0.06mmol, 0.2 equivalent) and NMP (0.60mmol, 2.0 equivalent) to a 10mL Schlenk tube equipped with a magnetic stirrer. Vacuum with a pump and fill with nitrogen three times. Then, add 1.0mL of tetrahydrofuran and alkyl Grignard reagent under N2 atmosphere. The mixture is reacted at 0°C for 1 hour. After reaching room temperature, the mixture is diluted with ethyl acetate, an appropriate amount of water is added, and then extracted three times with ethyl acetate, the organic phase is collected, and an appropriate amount of anhydrous Na2SO4 is added to dehydrate the combined organic layer, and concentrated under reduced pressure. The crude product is separated by column chromatography on silica gel to obtain a purified olefin derivative.

[0069] Example 30:

[0070] Add (Z)-3,3,3-trifluoro-1-phenylprop-1-en-2-yl 2-phenylacetate (0.30mmol, 1.0 equivalent) and DMP (0.60mmol, 2.0 equivalent) to a 10mL Schlenk tube equipped with a magnetic stirrer. Vacuum with a pump and fill with nitrogen three times. Then, add 1.0mL of 1,4-dioxane under N2 atmosphere. The mixture is reacted at 100°C for 12 hours. After cooling to room temperature, the mixture is diluted with ethyl acetate, an appropriate amount of water is added, and then extracted three times with ethyl acetate, the organic phase is collected, and an appropriate amount of anhydrous Na2SO4 is added to dehydrate the combined organic layers, and concentrated under reduced pressure. The crude product is separated by column chromatography on silica gel to obtain purified trifluoromethyl diketone compounds.

[0071] The above-mentioned embodiments only express several implementation methods of the present invention, and the description thereof is relatively specific and detailed, but it cannot be understood as limiting the scope of the patent of the present invention. It should be pointed out that, for ordinary technicians in this field, several variations and improvements can be made without departing from the concept of the present invention, which all belong to the protection scope of the present invention. Therefore, the protection scope of the patent of the present invention shall be subject to the attached claims.

Claims

1. A method for synthesizing (Z)-α-substituted trifluoromethyl enol esters using copper catalysis, characterized in that: The synthesis method is as follows: add 0.30mmol of carboxylic acid derivative, 0.03mmol of CuCl and 0.69mmol of NaI to a 10mL Schlenk tube equipped with a magnetic stirrer; evacuate with a pump and fill with nitrogen three times; then, add 1.0mL of ultra-dry solvent tetrahydrofuran and 0.6mmol of TMSCF3 under N2 atmosphere; stir the obtained mixture in a 70°C constant temperature oil bath for 12 hours; after cooling to room temperature, dilute the mixture with ethyl acetate, add an appropriate amount of water, and then extract with ethyl acetate three times, collect the organic phase, add an appropriate amount of anhydrous Na2SO4 for dehydration, combine the organic layers, and concentrate under reduced pressure; the crude product is separated by column chromatography on silica gel to obtain purified trifluoromethyl enol ester; the reaction formula is as follows: The carboxylic acid derivatives are selected from the following compounds: phenylacetic acid; methoxyphenylacetic acid, wherein the methyl group is located at the para position, meta position, or ortho position of the carboxyl group; Bromophenylacetic acid, wherein the bromine is located at the para position, meta position, or ortho position of the carboxyl group; Methylphenylacetic acid, wherein the methyl group is located at the para position, meta position or ortho position of the carboxyl group; Halogen-substituted phenylacetic acid, wherein the halogen is fluorine, chlorine or iodine; 3,4,5-trimethoxyphenylacetic acid; 4-phenoxyphenylacetic acid; 2-thiophenephenylacetic acid; 2-naphthophenylacetic acid, 2-(2,3-dihydrobenzofuran-6-yl)acetic acid; phenylpropionic acid; phenylbutyric acid; indomethacin; isoxacic acid; phenoxyacetic acid; Halogen-substituted phenoxyacetic acid, wherein the halogen is fluorine, bromine or iodine; Chlorine-substituted phenoxyacetic acid, wherein the chlorine is located at the para position or meta position of the carboxyl group; Methyl-substituted phenoxyacetic acid, wherein the methyl group is located at the para position, meta position, or ortho position of the carboxyl group; 4-tert-Butylphenoxyacetic acid; 4-isopropylphenylacetic acid; 2,6-dimethylphenoxyacetic acid; Methoxy-substituted phenoxyacetic acid, wherein the methoxy group is located at the para, meta, or ortho position of the carboxyl group; 2,3-dimethoxyphenoxyacetic acid; 4-trifluoromethoxyphenoxyacetic acid; 1-naphthyloxyacetic acid; 2-naphthyloxyacetic acid; phenylthioacetic acid; 2-phenylpropionic acid; m-chloro-2-phenylpropionic acid; Among them, the substituent R in the carboxylic acid compound 3 With R 4 With the substituent R in the trifluoromethyl enol ester 3 and R 4 Corresponding.

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