A method of carboxylic acid amide formation

Abstract

The application discloses a carboxylic acid amidation method and an amide compound prepared by the method. The preparation method takes an amine compound and a carboxylic acid compound as raw materials, takes an organic solvent as a solvent, and performs light irradiation under the condition that a photocatalyst, an alkali and sulfur hexafluoride exist, so as to perform a reaction in the organic solvent to obtain the amide compound. The reaction condition of the application is mild, the reaction raw materials (including the amine compound, the carboxylic acid compound and the alkali) are cheap and easy to obtain, the application has the characteristics of cost saving, environmental friendliness and industrial popularization. The method effectively activates SF6, a greenhouse gas, and fully utilizes the decomposition products of SF6 to realize the amidation reaction of the carboxylic acid, so that SF6 is changed from waste to treasure. The required raw materials are simple and easy to obtain, the reaction condition is simple, green and energy-saving, and the application has high application value.

Description

Technical Field

[0001] This invention relates to the field of organic intermediate synthesis technology, and specifically to a carboxylic acid amidation method. Background Technology

[0002] Amide reactions are among the most commonly used organic synthesis reactions. A study on drug synthesis showed that 65% of drug synthesis processes utilize amidation. Furthermore, amidated products play important roles in the biomedical, pharmaceutical, and food industries, and have wide applications in industrial products. For example, thioamides can modify peptide units and proteins; thioamide modification can significantly improve the stability and activity of peptide drugs. Tyramine-derived hydroxycinnamate in plant-based foods, due to its natural antioxidant properties, can be used as a food preservative. Amide greases, due to their excellent thermal stability, radiation resistance, and mechanical stability, are commonly used in nuclear power and aerospace fields. Currently, the synthetic amide compounds include:

[0003] Method 1: Use 3,4,5-trifluorophenylboronic acid as a catalyst to catalyze the amidation reaction of carboxylic acids and amines.

[0004]

[0005] This method is applicable not only to the reaction of primary and tertiary amines with carboxylic acids, but also to some special substrates with large steric hindrance and olefin groups. However, it requires high temperature (>100℃) and anhydrous conditions and suffers from low atom economy.

[0006] Method 2: Using two zirconium catalysts (ZrCp2Cl2 / ZrCl4), under toluene solvent and reflux conditions at 110°C, the amidation reaction of carboxylic acids and amines can be catalyzed efficiently.

[0007]

[0008] This method has high yields and can synthesize two drug molecules, acetaminophen and moclobemide, in relatively high yields. However, it introduces metal compounds and requires high-temperature conditions.

[0009] Method 3: Secondary amides were synthesized by using an active ester as an acyl source and zinc powder as a catalyst under microwave heating in DMF solvent or heating in THF solvent.

[0010]

[0011] This reaction is characterized by its simplicity, high efficiency, environmental friendliness, and reusable catalyst. However, it has a narrow substrate applicability and generates alcohols, which poses significant challenges to the separation of subsequent products.

[0012] Based on the above analysis, there is still a need to develop a carboxylic acid amidation method that uses readily available raw materials, is easy to operate, has a high reaction yield, good functional group tolerance, is environmentally friendly, and is easy to promote in industrial production.

[0013] SF6 gas is a colorless, odorless, non-toxic, non-flammable, and non-corrosive gas at normal temperature and pressure. It is an inert gas with high stability, not decomposing even at high temperatures of 500-600℃, and does not react with acids, alkalis, or water. It is also an insulating gas with excellent insulating properties, used to extinguish high-voltage electric arcs, hence its widespread use in the power industry. However, SF6 has a powerful greenhouse effect, with a global warming potential 23,900 times that of CO2. Furthermore, because SF6 is a synthetic gas with remarkably stable chemical properties, it is extremely difficult to decompose, and its natural atmospheric lifespan can reach over three thousand years. As it accumulates in the atmosphere, its greenhouse effect continues to intensify. Therefore, SF6 emissions are strictly limited, and the large quantities of SF6 stored in the power sector face immense pressure in terms of disposal. Summary of the Invention

[0014] The technical problem to be solved by the present invention is to provide a simple, safe and green method for carboxylic acid amidation.

[0015] The present invention solves the above-mentioned technical problems through the following technical means:

[0016] A method for amidation of carboxylic acids, comprising using amine compounds and carboxylic acid compounds as raw materials, using an organic solvent as a solvent, and irradiating with light in the presence of a photocatalyst, an alkali, and sulfur hexafluoride, and reacting in the organic solvent to obtain amide compounds; wherein the organic solvent is one or a mixture of tetrahydrofuran, acetonitrile, and dichloromethane; and the amine compound is a secondary amine.

[0017] Preferably, the secondary amine has the following structural formula: R1 and R2 are both alkyl or substituted alkyl groups.

[0018] Preferably, the secondary amine is one of morpholine, diethylamine, hexahydropyridine, and L-proline methyl ester.

[0019] Preferably, the structural formula of the carboxylic acid compound is as follows: Wherein, R is one of aryl, substituted aryl, alkyl, substituted alkyl, or substituted alkenyl.

[0020] Preferably, the reaction formula of the present invention is as follows:

[0021]

[0022] Preferably, the substituents in the substituted alkyl, substituted aryl, and substituted alkenyl groups are all selected from C1-C1. 20 Alkyl, C2-C 20 alkenyl, C6-C 20 aryl, 5-10 membered heteroaryl containing one or more heteroatoms from 1-3 O, N, and S, C2-C 30 ester group, C3-C 20 And containing one or more heteroatoms from 1-5 O, N, S: cycloalkyl, trifluoromethyl, halogen, methoxy, dimethylamino, biphenyl, One or more of them.

[0023] Preferably, the carboxylic acid compound is one of 4-methoxybenzoic acid, 4-chlorobenzoic acid, 4-trifluoromethylbenzoic acid, benzoic acid, 4-(N,N-dimethylamino)benzoic acid, 4-vinylbenzoic acid, 1-benzofuran-5-carboxylic acid, p-methoxyphenylacetic acid, 4-biphenylacetic acid, 2-phenylacrylic acid, trans-2-phenylcyclopropane-carboxylic acid, BOC-glycine, probenecid, 4-phenylbenzoic acid, and (tert-butoxycarbonyl)glycine.

[0024] Preferably, the organic solvent is acetonitrile.

[0025] This invention is carried out in a system with a single organic solvent; other organic solvents may be present in the system if necessary, but from the perspective of reaction yield and simplicity of operation, it is preferable not to add other organic solvents, that is, to use a single organic solvent as the reaction solvent.

[0026] Preferably, the photocatalyst is one or more of organic photocatalysts or transition metal photocatalysts, or a mixture thereof.

[0027] Preferably, the organic photocatalyst is 4CZIPN, Mes-Acr + ClO4 — A mixture of one or two of them.

[0028] Preferably, the transition metal photocatalyst is one or a mixture of two of Ir[dF(CF3)ppy]2(dtbbpy)PF6 and Ir(dtbbpy)ppy2PF6.

[0029] Preferably, the photocatalyst is Ir[dF(CF3)ppy]2(dtbbpy)PF6.

[0030] Preferably, the alkali is an organic alkali.

[0031] Preferably, the organic base is a tertiary amine.

[0032] Preferably, the organic base is N,N-diisopropylethylamine. The yield of amide compounds is highest when the base is N,N-diisopropylethylamine.

[0033] Preferably, the molar ratio of the amine compound and the carboxylic acid compound is 1:1 to 20:1.

[0034] Preferably, the molar ratio of the amine compound to the carboxylic acid compound is 10:1.

[0035] Preferably, the molar ratio of the carboxylic acid compound to the photocatalyst is 100:0.2-1.

[0036] Preferably, the molar ratio of the carboxylic acid compound to the photocatalyst is 100:0.5.

[0037] Preferably, the molar ratio of the carboxylic acid compound to the base is 1:1 to 1:10.

[0038] Preferably, the molar ratio of the carboxylic acid compound to the base is 1:5.

[0039] Preferably, during the illumination process, blue light with a wavelength of 450-480nm is used as the light source.

[0040] Preferably, blue light with a wavelength of 465nm is used as the light source.

[0041] Preferably, the SF6 gas pressure is 1 atm during the irradiation process. The yield of amide compounds is highest when the gas pressure is 1 atm.

[0042] Preferably, during the light irradiation process, the reaction temperature is 0–50°C and the time is 5–48 h.

[0043] Preferably, during the light irradiation process, the reaction temperature is room temperature and the time is 20 hours.

[0044] The reaction temperature and reaction time of this invention can also be determined by technicians according to different amine compounds and carboxylic acid compounds, based on actual needs.

[0045] Preferably, the ratio of the carboxylic acid compound to the solvent is 0.5–0.1 mmol: 1 mL.

[0046] Preferably, the ratio of the carboxylic acid compound to the solvent is 0.17 mmol:1 mL. The yield of the amide compound is highest when the ratio is 0.17 mmol:1 mL.

[0047] Preferably, during the reaction, the decomposition products of SF6 are used as condensing agents.

[0048] This invention is a widely applicable method for the amidation of carboxylic acids. This method is suitable for the synthesis of various amide compounds and their derivatives, and has good tolerance to aryl carboxylic acids, alkyl carboxylic acids, substituted alkyl carboxylic acids, and heteroaryl carboxylic acids. Therefore, there are no particularly strict limitations on the types of carboxylic acid compounds.

[0049] The present invention also proposes an amide compound prepared by the aforementioned carboxylic acid amidation method.

[0050] The advantages of this invention are:

[0051] In this invention, readily available amines and carboxylic acids are used as reaction substrates, commercially available Ir[dF(CF3)ppy]2(dtbbpy)PF6 is used as a photocatalyst, and inexpensive and readily available N,N-diisopropylethylamine is used as a base. Amide compounds are synthesized simply and efficiently under SF6 gas. Compared with other methods for synthesizing amide compounds, this invention offers mild reaction conditions, uses readily available and inexpensive raw materials (including amines, carboxylic acids, and N,N-diisopropylethylamine), and features cost savings, environmental friendliness, and industrial applicability. This method effectively activates and utilizes SF6, a greenhouse gas, fully leveraging SF6 decomposition products to achieve the amidation reaction of carboxylic acids, turning SF6 waste into a valuable resource. The required raw materials are simple and readily available, the reaction conditions are simple, green, and energy-saving, and it has high application value.

[0052] This invention is applicable to a variety of carboxyl-containing compounds and has successfully synthesized a variety of amide drug molecules. It can be widely used in drug synthesis and total synthesis of natural products in industry and academia, and has high application value. Attached Figure Description

[0053] Figure 1 The 1H NMR spectrum of (4-methoxyphenyl)(morpholino) methyl ketone described in Example 1 of this invention;

[0054] Figure 2 The carbon NMR spectrum of (4-methoxyphenyl)(morpholino) methyl ketone described in Example 1 of this invention;

[0055] Figure 3 The 1H NMR spectrum of (4-chlorophenyl)(morpholino) methyl ketone described in Example 2 of this invention;

[0056] Figure 4 The carbon NMR spectrum of (4-chlorophenyl)(morpholino) methyl ketone described in Example 2 of this invention;

[0057] Figure 5 The 1H NMR spectrum of morpholino(4-(trifluoromethyl)phenyl) ketone described in Example 3 of this invention;

[0058] Figure 6 The carbon NMR spectrum of morpholino (4-(trifluoromethyl)phenyl) ketone described in Example 3 of this invention;

[0059] Figure 7 The NMR fluorine spectrum of morpholino (4-(trifluoromethyl)phenyl) ketone described in Example 3 of this invention;

[0060] Figure 8 The 1H NMR spectrum of morpholino(phenyl) methyl ketone described in Example 4 of this invention;

[0061] Figure 9 The carbon NMR spectrum of morpholino(phenyl) methyl ketone described in Example 4 of this invention;

[0062] Figure 10 The 1H NMR spectrum of (4-(dimethylamino)phenyl)(morpholino) methyl ketone described in Example 5 of this invention;

[0063] Figure 11 The carbon NMR spectrum of (4-(dimethylamino)phenyl)(morpholino) methyl ketone described in Example 5 of this invention;

[0064] Figure 12 The 1H NMR spectrum of morpholino (4-vinylphenyl) methyl ketone described in Example 6 of this invention;

[0065] Figure 13 The carbon NMR spectrum of morpholino (4-vinylphenyl) methyl ketone described in Example 6 of this invention;

[0066] Figure 14 The 1H NMR spectrum of 2-([1,1'-biphenyl]-4-yl)-1-morpholinoethane-1-one described in Example 7 of this invention;

[0067] Figure 15 The carbon NMR spectrum of 2-([1,1'-biphenyl]-4-yl)-1-morpholinoethane-1-one described in Example 7 of this invention;

[0068] Figure 16 The 1H NMR spectrum of 1-morpholino-2-phenylpropyl-2-en-1-one described in Example 8 of this invention;

[0069] Figure 17 The carbon NMR spectrum of 1-morpholino-2-phenylpropyl-2-en-1-one described in Example 8 of this invention;

[0070] Figure 18 The 1H NMR spectrum of morpholino((1R,2R)-2-phenylcyclopropyl) methyl ketone described in Example 9 of this invention;

[0071] Figure 19The carbon NMR spectrum of morpholino((1R,2R)-2-phenylcyclopropyl) methyl ketone described in Example 9 of this invention;

[0072] Figure 20 The 1H NMR spectrum of (2-morpholino-2-oxyethyl)carbamate described in Example 10 of this invention;

[0073] Figure 21 The carbon NMR spectrum of (2-morpholino-2-oxyethyl)carbamate tert-butyl ester described in Example 10 of this invention;

[0074] Figure 22 The 1H NMR spectrum of N-butyl-4-(morpholino-4-carbonyl)-N-propylbenzenesulfonamide described in Example 11 of this invention;

[0075] Figure 23 The carbon NMR spectrum of N-butyl-4-(morpholino-4-carbonyl)-N-propylbenzenesulfonamide described in Example 11 of this invention;

[0076] Figure 24 The 1H NMR spectrum of N-butyl-[1,1'-biphenyl]-4-carboxamide described in Example 12 of this invention;

[0077] Figure 25 The carbon NMR spectrum of N-butyl-[1,1'-biphenyl]-4-carboxamide described in Example 12 of this invention;

[0078] Figure 26 The 1H NMR spectrum of N,N-diethyl-3-methylbenzamide described in Example 13 of this invention;

[0079] Figure 27 The carbon NMR spectrum of N,N-diethyl-3-methylbenzamide described in Example 13 of this invention;

[0080] Figure 28 The 1H NMR spectrum of N,N-diethyl-2-(naphth-1-yloxy)propionamide described in Example 14 of this invention;

[0081] Figure 29 The carbon NMR spectrum of N,N-diethyl-2-(naphth-1-yloxy)propionamide described in Example 14 of this invention;

[0082] Figure 30 The 1H NMR spectrum of benzodioxane-6-(1-piperidinyl)formamide described in Example 15 of this invention;

[0083] Figure 31 This is the carbon NMR spectrum of benzodioxane-6-(1-piperidinyl)formamide described in Example 15 of the present invention.

[0084] Figure 32 The 1H NMR spectrum of (tert-butyloxycarbonyl)glycero-L-proline methyl ester described in Example 16 of this invention;

[0085] Figure 33 The image shows the carbon NMR spectrum of (tert-butoxycarbonyl)glycero-L-proline methyl ester described in Example 16 of this invention. Detailed Implementation

[0086] To make the objectives, technical solutions, and advantages of the embodiments of the present invention clearer, the technical solutions of the embodiments of the present invention will be clearly and completely described below in conjunction with the embodiments of the present invention. Obviously, the described embodiments are only some embodiments of the present invention, not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0087] Unless otherwise specified, all test materials and reagents used in the following examples are commercially available.

[0088] Unless otherwise specified in the embodiments, the techniques or conditions described in the literature in this field or in accordance with the product manual may be followed.

[0089] In this invention, "amide compounds" have the meaning commonly understood by those skilled in the art, namely, organic compounds in which the hydroxyl group of a carboxylic acid is replaced by an amino or amine group.

[0090] All raw materials used in the following specific examples are commercially available, and each reagent is purified using methods known in the art when necessary.

[0091] 1 H NMR and 13 All C NMR measurements were performed using a Bruker Avance 400 spectrometer. The test temperature was room temperature, and the solvent was deuterated chloroform. (Reference selection follows.) 1 ¹H NMR: CHCl₃ was 7.260 ppm; 13 C NMR: CHCl3 was 77,000 ppm.

[0092] Example 1

[0093] Synthesis of (4-methoxyphenyl)(morpholino) methyl ketone

[0094] 4-Methoxybenzoic acid (76.0 mg, 1 equivalent) and Ir[dF(CF3)ppy]2(dtbbpy)PF6 (2.8 mg) were added to a 12 mL headspace vial with a PTFE gasket. After evacuation, an SF6 balloon was inserted, followed by the addition of 3.0 mL of anhydrous acetonitrile, and bubbling for 3 minutes. Morpholine (437.3 μL, 10 equivalent) and N,N-diisopropylethylamine (434.6 μL, 5 equivalent) were then added. The reaction system was irradiated under a 15 W, 465 nm blue LED light source and stirred for 20 hours. After the reaction, the organic solvent was removed under vacuum, and (4-methoxyphenyl)(morpholino) methyl ketone (90.6 mg, 82%) was obtained by silica gel column chromatography (petroleum ether:ethyl acetate volume ratio = 3:1).

[0095] The NMR spectrum of the product (4-methoxyphenyl)(morpholino) methyl ketone is shown below. Figure 1 and 2 As shown, the NMR data are as follows: 1 HNMR (400MHz, CDCl3) δ7.35–7.33(m,2H),6.88–6.86(m,2H),3.78(s,3H),3.64–3.59(m,8H)ppm. 13 C NMR (101MHz, CDCl3) δ170.2,160.7,129.1,127.2,113.6,66.7,55.2ppm.

[0096] Example 2

[0097] Synthesis of (4-chlorophenyl)(morpholino) methyl ketone

[0098] 4-Chlorobenzoic acid (78.3 mg, 1 equivalent) and Ir[dF(CF3)ppy]2(dtbbpy)PF6 (2.8 mg) were added to a 12 mL headspace vial with a PTFE gasket. After evacuation, an SF6 balloon was inserted, followed by the addition of 3.0 mL of anhydrous acetonitrile, and bubbling for 3 minutes. Morpholine (437.3 μL, 10 equivalent) and N,N-diisopropylethylamine (434.6 μL, 5 equivalent) were then added. The reaction system was irradiated under a 15 W, 465 nm blue LED light source and stirred for 20 hours. After the reaction was complete, the organic solvent was removed under vacuum, and 51.8 mg of (4-chlorophenyl)(morpholino) methyl ketone was obtained by silica gel column chromatography (petroleum ether:ethyl acetate volume ratio = 3:1), with a yield of 46%.

[0099] The NMR spectrum of the product (4-chlorophenyl)(morpholino) methyl ketone is shown below. Figure 3 and 4 As shown, the NMR data are as follows:1 H NMR (400MHz, CDCl3) δ7.38–7.32(m,4H),3.90–3.43(m,8H)ppm. 13 C NMR (101MHz, CDCl3) δ169.2, 135.9, 133.5, 128.8, 128.6, 66.7ppm.

[0100] Example 3

[0101] Synthesis of Morpholinyl (4-(trifluoromethyl)phenyl) ketone

[0102] 4-Trifluoromethylbenzoic acid (95.1 mg, 1 equivalent) and Ir[dF(CF3)ppy]2(dtbbpy)PF6 (2.8 mg) were added to a 12 mL headspace vial with a PTFE gasket. After evacuation, an SF6 balloon was inserted, followed by the addition of 3.0 mL of anhydrous acetonitrile, and bubbling for 3 minutes. Morpholine (437.3 μL, 10 equivalent) and N,N-diisopropylethylamine (434.6 μL, 5 equivalent) were then added. The reaction system was irradiated under a 15 W, 465 nm blue LED light source and stirred for 20 hours. After the reaction was complete, the organic solvent was removed under vacuum, and morpholino(4-(trifluoromethyl)phenyl) ketone (57.0 mg, 44% yield) was obtained by silica gel column chromatography (petroleum ether:ethyl acetate volume ratio = 3:1).

[0103] The NMR spectrum of the product morpholino(4-(trifluoromethyl)phenyl) ketone is shown below. Figure 5-7 As shown, the NMR data are as follows: 1 HNMR(400MHz, CDCl3)δ:7.68–7.66(m,2H),7.52–7.50(m,2H),3.77–3.38(m,8H)ppm. 13 CNMR(101MHz,CDCl3)δ168.8,138.8,131.7(q,J C-F =33.0Hz), 127.4, 125.6(q,J) C-F =3.7Hz), 123.6(q,J C-F =273.4Hz),66.7,48.0,42.5ppm. 19 F NMR(376MHz, CDCl3)δ–63.3ppm.

[0104] Example 4

[0105] Synthesis of Morpholinyl (Phenyl)methyl ketone

[0106] Benzoic acid (61.0 mg, 1 equivalent) and Ir[dF(CF3)ppy]2(dtbbpy)PF6 (2.8 mg) were added to a 12 mL headspace vial with a PTFE gasket. After evacuation, an SF6 balloon was inserted, followed by the addition of 3.0 mL of anhydrous acetonitrile, and bubbling for 3 minutes. Morpholine (437.3 μL, 10 equivalent) and N,N-diisopropylethylamine (434.6 μL, 5 equivalent) were then added. The reaction system was irradiated under a 15 W, 465 nm blue LED light source and stirred for 20 hours. After the reaction was complete, the organic solvent was removed under vacuum, and morpholino(phenyl) methyl ketone (86.0 mg) was obtained by silica gel column chromatography (petroleum ether:ethyl acetate volume ratio = 3:1), with a yield of 90%.

[0107] The NMR spectrum of the product morpholino(phenyl) methyl ketone is as follows: Figure 8 and 9 As shown, the NMR data are as follows: 1 H NMR (400MHz, CDCl3) δ7.38 (s, 5H), 3.76–3.42 (m, 8H)ppm. 13 C NMR (101MHz, CDCl3) δ170.3, 135.2, 129.7, 128.4, 126.9, 66.7ppm.

[0108] Example 5

[0109] Synthesis of (4-(dimethylamino)phenyl)(morpholino)methyl ketone

[0110] 4-(N,N-dimethylamino)benzoic acid (82.5 mg, 1 equivalent) and Ir[dF(CF3)ppy]2(dtbbpy)PF6 (2.8 mg) were added to a 12 mL headspace vial with a PTFE gasket. After evacuation, an SF6 balloon was inserted, followed by the addition of 3.0 mL of anhydrous acetonitrile, and bubbling for 3 minutes. Morpholine (437.3 μL, 10 equivalent) and N,N-diisopropylethylamine (434.6 μL, 5 equivalent) were then added. The reaction system was irradiated under a 15 W, 465 nm blue LED light source and stirred for 20 hours. After the reaction was complete, the organic solvent was removed under vacuum, and (4-(dimethylamino)phenyl)(morpholino)methyl ketone (99.5 mg, 85% yield) was obtained by silica gel column chromatography (petroleum ether:ethyl acetate volume ratio = 3:1).

[0111] The NMR spectrum of the product (4-(dimethylamino)phenyl)(morpholino) methyl ketone is shown below. Figure 10 and 11 As shown, the NMR data are as follows: 1H NMR (400MHz, CDCl3) δ7.34–7.32(m,2H),6.65–6.63(m,2H),3.65–3.63(m,8H),2.96(s,6H)ppm. 13 C NMR (101MHz, CDCl3) δ171.0,151.4,129.2,121.6,111.0,66.8,40.0ppm.

[0112] Example 6

[0113] Synthesis of Morpholinyl (4-vinylphenyl) methyl ketone

[0114] 4-Vinylbenzoic acid (74.0 mg, 1 equivalent) and Ir[dF(CF3)ppy]2(dtbbpy)PF6 (2.8 mg) were added to a 12 mL headspace vial with a PTFE gasket. After evacuation, an SF6 balloon was inserted, followed by the addition of 3.0 mL of anhydrous acetonitrile, and bubbling for 3 minutes. Morpholine (437.3 μL, 10 equivalent) and N,N-diisopropylethylamine (434.6 μL, 5 equivalent) were then added. The reaction system was irradiated under a 15 W, 465 nm blue LED light source and stirred for 20 hours. After the reaction was complete, the organic solvent was removed under vacuum, and morpholino(4-vinylphenyl) methyl ketone (69.4 mg, 64% yield) was obtained by silica gel column chromatography (petroleum ether:ethyl acetate volume ratio = 3:1).

[0115] The NMR spectrum of the product morpholino(4-vinylphenyl) methyl ketone is shown below. Figure 12 and 13 As shown, the NMR data are as follows: 1 HNMR (400MHz, CDCl3) δ7.44–7.35(m,4H),6.74–6.67(m,1H),5.79(d,J=17.6Hz,1H),5.31(d,J=10.8Hz,1H),3.74–3.46(m,8H)ppm. 13 C NMR (101MHz, CDCl3) δ170.1,139.0,135.8,134.3,127.4,126.2,115.4,66.8ppm.

[0116] Example 7

[0117] Synthesis of 2-([1,1'-biphenyl]-4-yl)-1-morpholinoethane-1-one

[0118] 106.1 mg of 4-biphenylacetic acid (1 equivalent) and 2.8 mg of Ir[dF(CF3)ppy]2(dtbbpy)PF6 were added to a 12 mL headspace vial with a PTFE gasket. After evacuation, an SF6 balloon was inserted, followed by the addition of 3.0 mL of anhydrous acetonitrile, and bubbling for 3 minutes. Then, 437.3 μL of morpholine (10 equivalent) and 434.6 μL of N,N-diisopropylethylamine (5 equivalent) were added. The reaction system was irradiated under a 15 W, 465 nm blue LED light source and stirred for 20 hours. After the reaction, the organic solvent was removed under vacuum, and 120.8 mg of 2-([1,1'-biphenyl]-4-yl)-1-morpholinoethane-1-one was obtained by silica gel column chromatography (petroleum ether:ethyl acetate volume ratio = 3:1), with a yield of 86%.

[0119] The NMR spectrum of the product 2-([1,1'-biphenyl]-4-yl)-1-morpholinoethane-1-one is shown below. Figure 14 and 15 As shown, the NMR data are as follows: 1 H NMR (400MHz, CDCl3) δ7.60–7.55(m,4H),7.45–7.40(m,2H),7.36–7.30(m,3H),3.77(s,2H),3.66(s,4H),3.54–3.47(m,4H)ppm. 13 C NMR (101MHz, CDCl3) δ169.5,140.5,139.7,133.7,128.9,128.7,127.4,127.2,126.9,66.7,66.4,46.4,42.1,40.3ppm.

[0120] Example 8

[0121] Synthesis of 1-morpholino-2-phenylpropyl-2-en-1-one

[0122] 2-Phenylacetic acid (74.1 mg, 1 equivalent) and Ir[dF(CF3)ppy]2(dtbbpy)PF6 (2.8 mg) were added to a 12 mL headspace vial with a PTFE gasket. After evacuation, an SF6 balloon was inserted, followed by the addition of 3.0 mL of anhydrous acetonitrile, and bubbling for 3 minutes. Morpholine (437.3 μL, 10 equivalent) and N,N-diisopropylethylamine (434.6 μL, 5 equivalent) were then added. The reaction system was irradiated under a 15 W, 465 nm blue LED light source and stirred for 20 hours. After the reaction was complete, the organic solvent was removed under vacuum, and 61.8 mg of 1-morpholino-2-phenylpropyl-2-en-1-one was obtained by silica gel column chromatography (petroleum ether:ethyl acetate volume ratio = 3:1), with a yield of 57%.

[0123] The NMR spectrum of the product 1-morpholino-2-phenylpropyl-2-en-1-one is shown below. Figure 16 and 17 As shown, the NMR data are as follows: 1 H NMR (400MHz, CDCl3) δ7.43–7.41(m,2H),7.39–7.29(m,3H),5.77(s,1H),5.38(s,1H),3.76–3.71(m,4H),3.49–3.35(m,4H)ppm. 13 C NMR (101MHz, CDCl3) δ169.4,144.4,135.3,128.9,128.7,125.6,114.5,66.8,47.2,41.9ppm.

[0124] Example 9

[0125] Synthesis of Morpholinyl ((1R,2R)-2-phenylcyclopropyl) methyl ketone

[0126] Trans-2-phenylcyclopropane-carboxylic acid (81.1 mg, 1 equivalent) and Ir[dF(CF3)ppy]2(dtbbpy)PF6 (2.8 mg) were added to a 12 mL headspace vial with a PTFE gasket. After evacuation, an SF6 balloon was inserted, followed by the addition of 3.0 mL of anhydrous acetonitrile, and bubbling for 3 minutes. Morpholine (437.3 μL, 10 equivalent) and N,N-diisopropylethylamine (434.6 μL, 5 equivalent) were then added. The reaction system was irradiated under a 15 W, 465 nm blue LED light source and stirred for 20 hours. After the reaction, the organic solvent was removed under vacuum, and morpholino((1R,2R)-2-phenylcyclopropane) methyl ketone (90% yield) was obtained by silica gel column chromatography (petroleum ether:ethyl acetate volume ratio = 3:1).

[0127] The NMR spectrum of the product morpholino((1R,2R)-2-phenylcyclopropyl) methyl ketone is shown below. Figure 18 and 19 As shown, the NMR data are as follows: 1 H NMR (400MHz, CDCl3) δ7.30–7.27(m,2H),7.22–7.18(m,1H),7.12–7.10(m,2H),3.70–3.6 2(m,8H),2.52–2.47(m,1H),1.96–1.91(m,1H),1.70–1.65(m,1H),1.32–1.27(m,1H)ppm. 13 C NMR (101MHz, CDCl3) δ170.6,140.7,128.5,126.3,126.0,66.7,45.9,42.5,25.5,22.9,16.2ppm.

[0128] Example 10

[0129] Synthesis of tert-butyl (2-morpholino-2-oxoethyl)carbamate

[0130] BOC-glycine (87.6 mg, 1 equivalent) and Ir[dF(CF3)ppy]2(dtbbpy)PF6 (2.8 mg) were added to a 12 mL headspace vial with a PTFE gasket. After evacuation, an SF6 balloon was inserted, followed by the addition of 3.0 mL of anhydrous acetonitrile, and bubbling for 3 minutes. Morpholine (437.3 μL, 10 equivalent) and N,N-diisopropylethylamine (434.6 μL, 5 equivalent) were then added. The reaction system was irradiated under a 15 W, 465 nm blue LED light source and stirred for 20 hours. After the reaction, the organic solvent was removed under vacuum, and 81.7 mg of (2-morpholino-2-oxyethyl)carbamate was obtained by silica gel column chromatography (petroleum ether:ethyl acetate volume ratio = 3:1), with a yield of 67%.

[0131] The NMR spectrum of the product (2-morpholino-2-oxoethyl) tert-butyl carbamate is shown below. Figure 20 and 21 As shown, the NMR data are as follows: 1 H NMR (400MHz, CDCl3) δ5.50(br,1H),3.93–3.92(m,2H),3.66–3.59(m,6H),3.38–3.36(m,2H),1.42(s,9H)ppm. 13C NMR (101MHz, CDCl3) δ167.0,155.7,79.6,66.6,66.2,44.7,42.1,42.0,28.3ppm.

[0132] Example 11

[0133] Synthesis of N-butyl-4-(morpholino-4-carbonyl)-N-propylbenzenesulfonamide

[0134] Probenecid (142.7 mg, 1 equivalent) and Ir[dF(CF3)ppy]2(dtbbpy)PF6 (2.8 mg) were added to a 12 mL headspace vial with a PTFE gasket. After evacuation, an SF6 balloon was inserted, followed by the addition of 3.0 mL of anhydrous acetonitrile, and bubbling for 3 minutes. Morpholine (437.3 μL, 10 equivalent) and N,N-diisopropylethylamine (434.6 μL, 5 equivalent) were then added. The reaction system was irradiated under a 15 W, 465 nm blue LED light source and stirred for 20 hours. After the reaction, the organic solvent was removed under vacuum, and N-butyl-4-(morpholine-4-carbonyl)-N-propylbenzenesulfonamide (99.1 mg, 56% yield) was obtained by silica gel column chromatography (petroleum ether:ethyl acetate volume ratio = 3:1).

[0135] The NMR spectrum of the product N-butyl-4-(morpholino-4-carbonyl)-N-propylbenzenesulfonamide is shown below. Figure 22 and 23 As shown, the NMR data are as follows: 1 H NMR (400MHz, CDCl3) δ7.85–7.83(m,2H),7.52–7.50(m,2H),3.77–3.37(m,8H),3.08–3.06(m,4H),1.59–1.50(m,4H),0.86(t,J=7.6Hz,6H)ppm. 13 C NMR (101MHz, CDCl3) δ168.7,141.5,139.0,127.6,127.3,66.7,50.0,22.0,11.1ppm.

[0136] Example 12

[0137] Synthesis of N-butyl-[1,1'-biphenyl]-4-carboxamide

[0138] 4-Phenylacetic acid (99.0 mg, 1 equivalent) and Ir[dF(CF3)ppy]2(dtbbpy)PF6 (2.8 mg) were added to a 12 mL headspace vial with a PTFE gasket. After evacuation, an SF6 balloon was inserted, followed by the addition of 3.0 mL of anhydrous acetonitrile, and bubbling for 3 minutes. Then, n-butylamine (494.2 μL, 10 equivalent) and N,N-diisopropylethylamine (434.6 μL, 5 equivalent) were added. The reaction system was irradiated under a 15 W, 465 nm blue LED light source and stirred for 20 hours. After the reaction was complete, the organic solvent was removed under vacuum, and N-butyl-[1,1'-biphenyl]-4-carboxamide (8.9 mg, 7% yield) was obtained by silica gel column chromatography (petroleum ether:ethyl acetate volume ratio = 5:1).

[0139] The NMR spectrum of the product N-butyl-[1,1'-biphenyl]-4-carboxamide is shown below. Figure 24 and 25 As shown, the NMR data are as follows: 1 HNMR(400MHz, CDCl3)δ7.84–7.82(m,2H),7.65–7.59(m,4H),7.48-7.44(m,2H),7.40-7.36(m,1H) ,6.21(br,1H),3.51-3.46(m,2H),1.66-1.59(m,2H),1.48-1.40(m,2H),0.97(t,J=7.3Hz,3H)ppm. 13 C NMR (101MHZ, CDCl3) δ167.2,144.1,140.0,133.5,128.9,127.9,127.3,127.2,127.2,39.8,31.7,20.2,13.8ppm.

[0140] Example 13

[0141] Synthesis of N,N-diethyl-3-methylbenzamide

[0142] 3-Methylbenzoic acid (68.0 mg, 1 equivalent) and Ir[dF(CF3)ppy]2(dtbbpy)PF6 (2.8 mg) were added to a 12 mL headspace vial with a PTFE gasket. After evacuation, an SF6 balloon was inserted, followed by the addition of 3.0 mL of anhydrous acetonitrile, and bubbling for 3 minutes. Then, diethylamine (517.3 μL, 10 equivalent) and N,N-diisopropylethylamine (434.6 μL, 5 equivalent) were added. The reaction system was irradiated under a 15 W, 465 nm blue LED light source and stirred for 20 hours. After the reaction was complete, the organic solvent was removed under vacuum, and N,N-diethyl-3-methylbenzamide (64.9 mg, 68% yield) was obtained by silica gel column chromatography (petroleum ether:ethyl acetate volume ratio = 3:1).

[0143] The NMR spectrum of the product N,N-diethyl-3-methylbenzamide is as follows: Figure 26 and 27 As shown, the NMR data are as follows: 1 HNMR (400MHz, CDCl3) δ7.15–7.11(m,1H),7.06–7.01(m,3H),3.40–3.12(m,4H),2.23(s,3H),1.12–0.97(m,4H)ppm. 13 C NMR (101MHz, CDCl3) δ170.9,137.7,136.8,129.3,127.7,126.4,122.6,42.8,38.6,20.9,13.7,12.4ppm.

[0144] Example 14

[0145] Synthesis of N,N-diethyl-2-(naphthalene-1-yloxy)propionamide

[0146] 2-(1-naphthoxy)propionic acid (108.1 mg, 1 equivalent) and Ir[dF(CF3)ppy]2(dtbbpy)PF6 (2.8 mg) were added to a 12 mL headspace vial with a PTFE gasket. After evacuation, an SF6 balloon was inserted, followed by the addition of 3.0 mL of anhydrous acetonitrile, and bubbling for 3 minutes. Then, diethylamine (517.3 μL, 10 equivalent) and N,N-diisopropylethylamine (434.6 μL, 5 equivalent) were added. The reaction system was irradiated under a 15 W, 465 nm blue LED light source and stirred for 20 hours. After the reaction was complete, the organic solvent was removed under vacuum, and N,N-diethyl-2-(naphth-1-yloxy)propionamide (89.4 mg, 66% yield) was obtained by silica gel column chromatography (petroleum ether:ethyl acetate volume ratio = 3:1).

[0147] The NMR spectrum of the product N,N-diethyl-2-(naphthalene-1-yloxy)propionamide is shown below. Figure 28 and 29 As shown, the NMR data are as follows: 1 H NMR (400MHz, CDCl3) δ8.31–8.29(m,1H),7.81–7.78(m,1H),7.51–7.43(m,3H),7.35–7.32(m,2H),6.83–6.82(m ,1H),5.12(q,J=6.8Hz,1H),3.62–3.53(m,1H),3.46–3.35(m,3H),1.73(d,J=6.8Hz,1H),1.13–0.98(m,6H)ppm. 13 C NMR (101MHz, CDCl3) δ170.2,153.1,134.5,127.4,126.4,125.7,125.6,125.3,122.0,120.9,105.7,41.0,40.3,17.9,14.1,12.6ppm.

[0148] Example 15

[0149] Synthesis of benzodioxane-6-(1-piperidinyl)carboxamide

[0150] 2,3-Dihydro-1,4-benzodialkyl-6-carboxylic acid (90.1 mg, 1 equivalent) and Ir[dF(CF3)ppy]2(dtbbpy)PF6 (2.8 mg) were added to a 12 mL headspace vial with a PTFE gasket. After evacuation, an SF6 balloon was inserted, followed by the addition of 3.0 mL of anhydrous acetonitrile, and bubbling for 3 minutes. Then, hexahydropyridine (493.9 μL, 10 equivalent) and N,N-diisopropylethylamine (434.6 μL, 5 equivalent) were added. The reaction system was irradiated under a 15 W, 465 nm blue LED light source and stirred for 20 hours. After the reaction was complete, the organic solvent was removed under vacuum, and 42.0 mg of benzodioxane-6-(1-piperidinyl)carboxamide was obtained by silica gel column chromatography (petroleum ether:ethyl acetate volume ratio = 3:1), with a yield of 34%.

[0151] The NMR spectrum of the product benzodioxane-6-(1-piperidinyl)carboxamide is shown below. Figure 30 and 31 As shown, the NMR data are as follows: 1 H NMR (400MHz, CDCl3) δ6.92–6.83(m,3H),4.26(s,4H),3.63–3.39(m,4H),1.65–1.57(m,6H)ppm. 13C NMR (101MHz, CDCl3) δ169.7,144.6,143.2,129.5,120.4,117.1,116.4,64.4,64.2,24.6ppm.

[0152] Example 16

[0153] Synthesis of (tert-butoxycarbonyl)glycero-L-proline methyl ester

[0154] (tert-Butoxycarbonyl)glycine (87.5 mg, 1 equiv.), L-proline methyl ester (645.4 mg, 10 equiv.), and Ir[dF(CF3)ppy]2(dtbbpy)PF6 (2.8 mg) were added to a 12 mL headspace vial with a PTFE gasket. After evacuation, an SF6 balloon was inserted, followed by the addition of 3.0 mL of anhydrous acetonitrile and bubbling for 3 minutes. Then, N,N-diisopropylethylamine (434.6 μL, 5 equiv.) was added. The reaction system was irradiated under a 15 W, 465 nm blue LED light source and stirred for 20 hours. After the reaction was complete, the organic solvent was removed under vacuum, and 249.0 mg of (tert-Butoxycarbonyl)glycerol-L-proline methyl ester was obtained by silica gel column chromatography (petroleum ether:ethyl acetate volume ratio = 1:2), with a yield of 87%.

[0155] The NMR spectrum of the product (tert-butyloxycarbonyl)glycero-L-proline methyl ester is shown below. Figure 32 and 33 As shown, the NMR data are as follows: 1 H NMR (400MHz, CDCl3) δ5.38(br,1H),4.49–4.47(m,1H),3.97–3.84(m,2H),3.69(s,3H),3.58–3.40(m,2H),2.18–1.96(m,4H),1.40(s,9H)ppm. 13 C NMR (101MHz, CDCl3) δ172.2,167.3,155.7,79.5,58.7,52.2,45.7,42.9,28.9,28.2,24.5ppm.

[0156]

[0157]

[0158] In the above embodiments, irradiation was performed at room temperature under SF6 gas at one atmosphere.

[0159] As shown in Examples 1-16, this invention uses readily available carboxylic acids and amines as reaction substrates, commercially available Ir[dF(CF3)ppy]2(dtbbpy)PF6 as a photocatalyst, and inexpensive and readily available N,N-diisopropylethylamine as a base. Under SF6 gas at one atmosphere, at room temperature, and using 15W 465nm blue light as the light source, amide compounds are synthesized simply and efficiently. This method exhibits good tolerance to aryl, heteroaryl carboxylic acids, aliphatic carboxylic acids, and amino acids, and shows good reactivity with different amine compounds. There are no particularly strict limitations on the number and type of substituents in the carboxylic acids and amines. Furthermore, this synthetic method has been applied to the synthesis of amide drugs, successfully yielding DEET, dichlorvos, and CX546. Therefore, it is a general synthetic method for amide compounds that is mild, simple to operate, and easy to industrially promote. Moreover, this method effectively activates and utilizes SF6, a greenhouse gas, fully utilizing the decomposition products of SF6 to achieve the amidation reaction of carboxylic acids, turning SF6 waste into a valuable resource.

[0160] Comparative Example 1

[0161] Following the method of Example 12, the reaction conditions were changed, and the changed conditions and yield results are shown in the table below:

[0162]

[0163] Serial Number amine compounds <![CDATA[SF6]]> solvent Yield (%) 1 Morpholine have THF 68 2 Morpholine have MeCN 96 3 Morpholine have DCM 63 4 Morpholine have DMF Trace 5 Morpholine have DMSO Trace 6 Morpholine none MeCN Trace 7 n-Butylamine have MeCN 7 8 p-Toluidine have MeCN Trace

[0164] Standard conditions: 1 (0.5 mmol), 2 (5 mmol), Ir[dF(CF3)ppy]2(dtbbpy)PF6 (0.0025 mmol), DIPEA (2.5 mmol), solvent (3 mL), room temperature, reaction time 20 hours.

[0165] The above embodiments are only used to illustrate the technical solutions of the present invention, and are not intended to limit it. Although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art should understand that modifications can still be made to the technical solutions described in the foregoing embodiments, or equivalent substitutions can be made to some of the technical features. Such modifications or substitutions do not cause the essence of the corresponding technical solutions to deviate from the spirit and scope of the technical solutions of the embodiments of the present invention.

Claims

1. A method of carboxylic acid amidation, characterized by: It uses amine compounds and carboxylic acid compounds as raw materials, and an organic solvent as the solvent. Under the conditions of photocatalyst, alkali and sulfur hexafluoride, the reaction is carried out in the organic solvent to obtain amide compounds. The organic solvent is one or a mixture of tetrahydrofuran, acetonitrile and dichloromethane; the amine compound is a secondary amine; the photocatalyst is one or a mixture of two of Ir[dF(CF3)ppy]2(dtbbpy)PF6 and Ir(dtbbpy)ppy2PF6; during the illumination process, blue light with a wavelength of 450-480nm is used as the light source.

2. The carboxamide method according to claim 1, characterized in that: The secondary amine has a structural formula of wherein R1 and R2 are each one of an alkyl group, a substituted alkyl group.

3. The carboxamide method of claim 1, wherein: The secondary amine is one of morpholine, diethylamine, hexahydropyridine, and L-proline methyl ester.

4. The carboxamide method of claim 1, wherein: The structural formula of the carboxylic acid compound is as follows: Wherein, R is one of aryl, substituted aryl, alkyl, substituted alkyl, and substituted alkenyl; the substituents in the substituted alkyl, substituted aryl, and substituted alkenyl groups are all selected from C1-C1. 20 Alkyl, C2-C 20 alkenyl, C6-C 20 aryl, 5-10 membered heteroaryl containing one or more heteroatoms from 1-3 O, N, and S, C2-C 30 ester group, C3-C 20 And containing one or more heteroatoms from 1-5 O, N, S: cycloalkyl, trifluoromethyl, halogen, methoxy, dimethylamino, biphenyl, , One or more of them.

5. The carboxamide method of claim 1, wherein: The carboxylic acid compound is one of the following: 4-methoxybenzoic acid, 4-chlorobenzoic acid, 4-trifluoromethylbenzoic acid, benzoic acid, 4-(N,N-dimethylamino)benzoic acid, 4-vinylbenzoic acid, 1-benzofuran-5-carboxylic acid, p-methoxyphenylacetic acid, 4-biphenylacetic acid, 2-phenylacrylic acid, trans-2-phenylcyclopropane-carboxylic acid, BOC-glycine, probenecid, 4-phenylbenzoic acid, and (tert-butyloxycarbonyl)glycine.

6. The carboxamide method of claim 1, wherein: The organic solvent is acetonitrile.

7. The carboxamide method of claim 1, wherein: The photocatalyst is Ir[dF(CF3)ppy]2(dtbbpy)PF6.

8. The carboxamide method of claim 1, wherein: The alkali is an organic alkali.

9. The carboxamide method according to claim 8, characterized in that: The organic base is N,N-diisopropylethylamine.

10. The carboxamide method of claim 1, wherein: The molar ratio of the amine compounds and carboxylic acid compounds is 1:1 to 20:

1.

11. The carboxamide method of claim 10, wherein: The molar ratio of the amine compound to the carboxylic acid compound is 10:

1.

12. The carboxamide process of claim 1, wherein: The molar ratio of the carboxylic acid compound to the photocatalyst is 100:0.2-1.

13. The carboxamide method of claim 12, wherein: The molar ratio of the carboxylic acid compound to the photocatalyst is 100:0.

5.

14. The carboxamide process of claim 1, wherein: The molar ratio of the carboxylic acid compound to the base is 1:1 to 1:

10.

15. The carboxamide method of claim 14, wherein: The molar ratio of the carboxylic acid compound to the base is 1:

5.

16. The carboxamide process of claim 1, wherein: During the illumination process, the SF6 gas pressure is 1 atm.

17. The carboxamide process of claim 1, wherein: During the light exposure process, the reaction temperature is 0~50℃ and the time is 5~48h.

18. The carboxamide method of claim 17, wherein: During the light exposure process, the reaction temperature was room temperature and the time was 20 hours.

19. The carboxamide process according to any one of claims 1 to 18, characterized in that: The ratio of the carboxylic acid compound to the solvent is 0.5~0.1 mmol: 1 mL.

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