Carboxylic acid amidation method

Abstract

According to the preparation method, an amine compound and a carboxylic acid compound are used as raw materials, an organic solvent is used as a solvent, illumination is carried out in the presence of a photocatalyst, alkali and sulfur hexafluoride, and a reaction is carried out in the organic solvent to obtain the amide compound. The reaction conditions are mild, the used reaction raw materials (including the amine compound, the carboxylic acid compound and the alkali) are cheap and easy to obtain, and the method has the characteristics of cost saving, environment friendliness and industrial popularization. According to the method, the greenhouse gas SF6 is effectively activated and utilized, the amidation reaction of carboxylic acid is realized by fully utilizing the decomposition product SF6, the SF6 is turned into wealth from waste, the required raw materials are simple and easy to obtain, the reaction conditions are simple and convenient, the method is green and energy-saving, and the method has relatively high application value.

Description

Technical Field

[0001] The invention relates to the technical field of organic intermediate synthesis, and in particular to a carboxylic acid amidation method. Background Art

[0002] Amidation reaction is the most commonly used organic synthesis reaction. A study on drug synthesis shows that 65% of drug synthesis processes use amidation reactions. In addition, amidation products play an important role in the biomedical, pharmaceutical and food industries, and are also widely used in industrial products. For example, sulfamide can modify peptide units and proteins, and sulfamide modification can significantly improve the stability and activity of peptide drugs; tyramine-derived hydroxycinnamamide in plant-based foods can be used as a food preservative due to its natural antioxidant effect; amide greases are often used in nuclear power and aerospace fields due to their excellent properties such as strong thermal stability, radiation resistance and mechanical stability. At present, the synthesis of amide compounds includes:

[0003] Method 1: Use 3,4,5-trifluorophenylboronic acid to catalyze the amidation reaction between carboxylic acid and amine.

[0004]

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

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

[0007]

[0008] This method has a high yield and can achieve the synthesis of two drug molecules, acetaminophen and moclobemide, with a relatively high yield, but this method introduces metal compounds and requires high temperature conditions.

[0009] Method 3: Using active ester as acyl source and zinc powder as catalyst, the synthesis of secondary amide was achieved under the conditions of microwave heating in DMF solvent or heating in THF solvent.

[0010]

[0011] The reaction has the following characteristics: simple, efficient, environmentally friendly and the catalyst can be reused. However, the substrate has a narrow scope of application and alcohol is also generated, which makes it very difficult to separate the subsequent products.

[0012] According to the above analysis, there is still a need to develop a carboxylic acid amidation method that has simple and readily available raw materials, simple operation, high reaction yield, good functional group tolerance, environmental friendliness, and is easy to promote in industrial production.

[0013] SF6 gas is a colorless, odorless, non-toxic, non-combustible, non-corrosive gas at room temperature and pressure. It is an inert gas with high stability. It does not decompose at high temperatures of 500-600°C and does not react with acids, alkalis, water, etc. It is also an insulating gas with excellent insulation properties and can be used to extinguish high-voltage arcs. Therefore, SF6 is widely used in the power sector. However, SF6 has a strong greenhouse effect, and its climate warming power is 23,900 times that of CO2. Secondly, because SF6 is an artificially synthesized gas with quite stable chemical properties, SF6 is extremely difficult to decompose and its natural lifespan in the atmosphere can be as long as more than 3,000 years. As it continues to accumulate in the atmosphere, the greenhouse effect it brings is also continuously increasing. Therefore, the emission of SF6 is strictly restricted, and the large amount of SF6 stored in the power sector faces tremendous pressure in treatment. Summary of the invention

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

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

[0016] A method for carboxylic acid amidation, which uses an amine compound and a carboxylic acid compound as raw materials, an organic solvent as solvent, irradiates with light in the presence of a photocatalyst, a base and sulfur hexafluoride, and reacts in the organic solvent to obtain an amide compound; wherein the organic solvent is a mixture of one or more of tetrahydrofuran, acetonitrile and dichloromethane; and the amine compound is a secondary amine.

[0017] Preferably, the structural formula of the secondary amine is Wherein, R1 and R2 are both alkyl and substituted alkyl.

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

[0019] Preferably, the structural formula of the carboxylic acid compound is Wherein, R is one of aryl, substituted aryl, alkyl, substituted alkyl, and 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 are all selected from C1-C 20 Alkyl, C2-C 20 Alkenyl, C6-C 20 Aryl, 5-10 membered heteroaryl containing 1-3 heteroatoms of one or more of O, N, S, C2-C 30 Ester group, C3-C 20 and containing 1 to 5 cycloalkyl, trifluoromethyl, halogen, methoxy, dimethylamino, biphenyl, One or more of .

[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-butyloxycarbonyl)glycine.

[0024] Preferably, the organic solvent is acetonitrile.

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

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

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

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

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

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

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

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

[0033] Preferably, the molar ratio of the amine compound to 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 1:1-1:10.

[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 450-480 nm is used as the light source.

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

[0041] Preferably, during the illumination process, the SF6 gas pressure is 1 atm. When the pressure is 1 atm, the yield of the amide compound is the highest.

[0042] Preferably, during the illumination process, the reaction temperature is 0 to 50° C. and the reaction time is 5 to 48 hours.

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

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

[0045] Preferably, the usage 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. When the ratio is 0.17 mmol: 1 mL, the yield of the amide compound is the highest.

[0047] Preferably, during the reaction, the decomposition products of SF6 serve as condensation agents.

[0048] The present invention is a carboxylic acid amidation method with a wide range of applications. The present method is applicable to the synthesis of various amide compounds and their derivatives, and has good tolerance for aromatic carboxylic acids, alkyl carboxylic acids, substituted alkyl carboxylic acids, and heteroaryl carboxylic acids. Therefore, there is actually no particularly strict restriction on the types of carboxylic acid compounds.

[0049] The present invention also provides an amide compound, which is prepared by adopting the carboxylic acid amidation method.

[0050] The advantages of the present invention are:

[0051] In the present invention, amines and carboxylic acid compounds that are easy to obtain are used as reaction substrates, commercially available Ir[dF(CF3)ppy]2(dtbbpy)PF6 and the like are used as photocatalysts, and cheap and easily available N,N-diisopropylethylamine and the like are used as bases, and amide compounds are simply and efficiently synthesized under SF6 gas. Compared with other methods for synthesizing amide compounds, the reaction conditions of the present invention are mild, the reaction raw materials used (including amine compounds and carboxylic acid compounds, N,N-diisopropylethylamine) are cheap and easily available, and the method has the characteristics of cost saving, environmental friendliness, and industrial promotion. The method effectively activates and utilizes SF6, a greenhouse gas, and makes full use of the decomposition products of SF6 to realize the amidation reaction of carboxylic acids, turning SF6 into treasure, the required raw materials are simple and easy to obtain, the reaction conditions are simple, and the reaction is green and energy-saving, and has a high application value.

[0052] The present 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. BRIEF DESCRIPTION OF THE DRAWINGS

[0053] Figure 1 This is the H NMR spectrum of (4-methoxyphenyl)(morpholinyl)methanone described in Example 1 of the present invention;

[0054] Figure 2 This is the NMR carbon spectrum of (4-methoxyphenyl)(morpholinyl)methanone described in Example 1 of the present invention;

[0055] Figure 3 This is the H NMR spectrum of (4-chlorophenyl)(morpholinyl)methanone described in Example 2 of the present invention;

[0056] Figure 4 This is the NMR carbon spectrum of (4-chlorophenyl)(morpholinyl)methanone described in Example 2 of the present invention;

[0057] Figure 5 This is the H NMR spectrum of the morpholinyl (4-(trifluoromethyl)phenyl)methanone described in Example 3 of the present invention;

[0058] Figure 6 This is the NMR carbon spectrum of morpholinyl (4-(trifluoromethyl)phenyl)methanone described in Example 3 of the present invention;

[0059] Figure 7 The NMR fluorine spectrum of morpholinyl (4-(trifluoromethyl)phenyl)methanone described in Example 3 of the present invention;

[0060] Figure 8 is the H NMR spectrum of the morpholinyl (phenyl) ketone described in Example 4 of the present invention;

[0061] Fig. 9 This is the NMR carbon spectrum of the morpholinyl (phenyl) ketone described in Example 4 of the present invention;

[0062] Fig.10 This is the H NMR spectrum of (4-(dimethylamino)phenyl)(morpholinyl)methanone described in Example 5 of the present invention;

[0063] Fig.11 This is the NMR carbon spectrum of (4-(dimethylamino)phenyl)(morpholinyl)methanone described in Example 5 of the present invention;

[0064] Fig.12 This is the H NMR spectrum of the morpholinyl (4-vinylphenyl) ketone described in Example 6 of the present invention;

[0065] Fig.13 This is the NMR carbon spectrum of morpholinyl (4-vinylphenyl) ketone described in Example 6 of the present invention;

[0066] Fig.14 This is the H NMR spectrum of 2-([1,1'-biphenyl]-4-yl)-1-morpholinoethane-1-one described in Example 7 of the present invention;

[0067] Fig.15 This is the NMR carbon spectrum of 2-([1,1'-biphenyl]-4-yl)-1-morpholinoethane-1-one described in Example 7 of the present invention;

[0068] Fig.16 This is the H NMR spectrum of 1-morpholinyl-2-phenylpropyl-2-en-1-one described in Example 8 of the present invention;

[0069] Fig.17 This is the NMR carbon spectrum of 1-morpholinyl-2-phenylpropyl-2-en-1-one described in Example 8 of the present invention;

[0070] Fig.18 This is the H NMR spectrum of the morpholinyl ((1R, 2R)-2-phenylcyclopropyl) ketone described in Example 9 of the present invention;

[0071] Fig.19This is the NMR carbon spectrum of morpholinyl ((1R, 2R)-2-phenylcyclopropyl) ketone described in Example 9 of the present invention;

[0072] Fig. 20 This is the H NMR spectrum of tert-butyl (2-morpholinyl-2-oxoethyl)carbamate described in Example 10 of the present invention;

[0073] Fig.21 This is the NMR carbon spectrum of tert-butyl (2-morpholinyl-2-oxoethyl)carbamate described in Example 10 of the present invention;

[0074] Fig. 22 This is the H NMR spectrum of N-butyl-4-(morpholine-4-carbonyl)-N-propylbenzenesulfonamide described in Example 11 of the present invention;

[0075] Fig.23 This is the NMR carbon spectrum of N-butyl-4-(morpholine-4-carbonyl)-N-propylbenzenesulfonamide described in Example 11 of the present invention;

[0076] Fig.24 is the H NMR spectrum of N-butyl-[1,1'-biphenyl]-4-carboxamide described in Example 12 of the present invention;

[0077] Fig.25 is the NMR carbon spectrum of N-butyl-[1,1'-biphenyl]-4-carboxamide described in Example 12 of the present invention;

[0078] Fig.26 is the H NMR spectrum of N,N-diethyl-3-methylbenzamide described in Example 13 of the present invention;

[0079] Fig. 27 is the NMR carbon spectrum of N, N-diethyl-3-methylbenzamide described in Example 13 of the present invention;

[0080] Fig.28 is the H NMR spectrum of N,N-diethyl-2-(naphthalen-1-yloxy)propionamide described in Example 14 of the present invention;

[0081] Fig.29 is the NMR carbon spectrum of N,N-diethyl-2-(naphthalen-1-yloxy)propionamide described in Example 14 of the present invention;

[0082] Fig.30 is the H NMR spectrum of benzodioxane-6-(1-piperidinyl)carboxamide described in Example 15 of the present invention;

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

[0084] Fig.32 This is the H NMR spectrum of (tert-butyloxycarbonyl)glyceryl-L-proline methyl ester described in Example 16 of the present invention;

[0085] Fig.33 This is the NMR carbon spectrum of (tert-butyloxycarbonyl)glyceryl-L-proline methyl ester described in Example 16 of the present invention. DETAILED DESCRIPTION

[0086] In order to make the purpose, technical solution and advantages of the embodiments of the present invention clearer, the technical solution in the embodiments of the present invention will be clearly and completely described in combination with the embodiments of the present invention. Obviously, the described embodiments are part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0087] Unless otherwise specified, the test materials and reagents used in the following examples can be obtained from commercial sources.

[0088] If no specific techniques or conditions are specified in the examples, they can be carried out according to the techniques or conditions described in the literature in the art or according to the product instructions.

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

[0090] The raw materials used in the following specific examples are all commercially available, and each reagent is purified by means known in the art before use when necessary.

[0091] 1 H NMR and 13 C NMR was measured using a Bruker Avance 400 spectrometer. The test temperature was room temperature, the solvent was deuterated chloroform, and the references were: 1 H NMR: CHCl3 7.260 ppm; 13 C NMR: CHCl3: 77.000 ppm.

[0092] Example 1

[0093] Synthesis of (4-methoxyphenyl)(morpholinyl)methanone

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

[0095] The NMR spectrum of the product (4-methoxyphenyl)(morpholinyl)methanone is as follows 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)(morpholinyl)methanone

[0098] 4-Chlorobenzoic acid (78.3 mg, 1 equiv.) and Ir[dF(CF3)ppy]2(dtbbpy)PF6 (2.8 mg) were added to a 12 mL headspace glass vial with a PTFE gasket, and then evacuated and an SF6 balloon was inserted. Then 3.0 mL of anhydrous acetonitrile was added and bubbled for 3 minutes. Subsequently, morpholine (437.3 μL, 10 equiv.) and N,N-diisopropylethylamine (434.6 μL, 5 equiv.) were added, and the reaction system was placed under a 15 W, 465 nm blue LED light source for irradiation and stirring for 20 hours. After the reaction was completed, the organic solvent was removed under vacuum, and 51.8 mg of (4-chlorophenyl)(morpholinyl)methanone 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)(morpholinyl)methanone is as follows 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)methanone

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

[0103] The NMR spectrum of the product morpholinyl (4-(trifluoromethyl)phenyl)methanone is as follows 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)Methanone

[0106] Benzoic acid (61.0 mg, 1 equiv.) and Ir[dF(CF3)ppy]2(dtbbpy)PF6 (2.8 mg) were added to a 12 mL headspace glass vial with a PTFE gasket, and then evacuated and an SF6 balloon was inserted. Then 3.0 mL of anhydrous acetonitrile was added and bubbled for 3 minutes. Subsequently, morpholine (437.3 μL, 10 equiv.) and N,N-diisopropylethylamine (434.6 μL, 5 equiv.) were added, and the reaction system was placed under a 15 W, 465 nm blue LED light source and stirred for 20 hours. After the reaction was completed, the organic solvent was removed under vacuum, and 86.0 mg of morpholinyl (phenyl) ketone 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 morpholinyl (phenyl) 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)(morpholinyl)methanone

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

[0111] The NMR spectrum of the product (4-(dimethylamino)phenyl)(morpholinyl)methanone is as follows Fig.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)methanone

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

[0115] The NMR spectrum of the product morpholinyl (4-vinylphenyl) ketone is as follows Fig.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] 4-Biphenylacetic acid (106.1 mg, 1 equiv.) and Ir[dF(CF3)ppy]2(dtbbpy)PF6 (2.8 mg) were added to a 12 mL headspace glass vial with a PTFE gasket, and then evacuated and an SF6 balloon was inserted, and then 3.0 mL of anhydrous acetonitrile was added and bubbled for 3 minutes. Subsequently, morpholine (437.3 μL, 10 equiv.) and N,N-diisopropylethylamine (434.6 μL, 5 equiv.) were added, and the reaction system was placed under a 15 W, 465 nm blue LED light source and stirred for 20 hours. After the reaction was completed, 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 as follows Fig.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-morpholinyl-2-phenylpropyl-2-en-1-one

[0122] 2-Phenyl acrylic acid (74.1 mg, 1 equiv.) and Ir[dF(CF3)ppy]2(dtbbpy)PF6 (2.8 mg) were added to a 12 mL headspace glass vial with a PTFE gasket, and then evacuated and an SF6 balloon was inserted, and then 3.0 mL of anhydrous acetonitrile was added and bubbled for 3 minutes. Subsequently, morpholine (437.3 μL, 10 equiv.) and N,N-diisopropylethylamine (434.6 μL, 5 equiv.) were added, and the reaction system was placed under a 15 W, 465 nm blue LED light source and stirred for 20 hours. After the reaction was completed, the organic solvent was removed under vacuum, and 61.8 mg of 1-morpholinyl-2-phenylpropyl-2-ene-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-morpholinyl-2-phenylpropyl-2-en-1-one is as follows Fig.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)methanone

[0126] Trans-2-phenylcyclopropane-carboxylic acid (81.1 mg, 1 equiv.) and Ir[dF(CF3)ppy]2(dtbbpy)PF6 (2.8 mg) were added to a 12 mL headspace glass vial with a PTFE gasket, and then evacuated and an SF6 balloon was inserted, and then 3.0 mL of anhydrous acetonitrile was added and bubbled for 3 minutes. Subsequently, morpholine (437.3 μL, 10 equiv.) and N,N-diisopropylethylamine (434.6 μL, 5 equiv.) were added, and the reaction system was placed under a 15 W, 465 nm blue LED light source and stirred for 20 hours. After the reaction was completed, the organic solvent was removed under vacuum, and 104.0 mg of morpholinyl ((1R, 2R)-2-phenylcyclopropyl) ketone was obtained by silica gel column chromatography (petroleum ether: ethyl acetate volume ratio = 3:1), with a yield of 90%.

[0127] The NMR spectrum of the product morpholinyl ((1R, 2R)-2-phenylcyclopropyl) ketone is as follows Fig.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-morpholinyl-2-oxyethyl)carbamate

[0130] BOC-glycine (87.6 mg, 1 equiv.) and Ir[dF(CF3)ppy]2(dtbbpy)PF6 (2.8 mg) were added to a 12 mL headspace glass vial with a PTFE gasket, and then evacuated and an SF6 balloon was inserted, and then 3.0 mL of anhydrous acetonitrile was added and bubbled for 3 minutes. Subsequently, morpholine (437.3 μL, 10 equiv.) and N,N-diisopropylethylamine (434.6 μL, 5 equiv.) were added, and the reaction system was placed under a 15 W, 465 nm blue LED light source and stirred for 20 hours. After the reaction was completed, the organic solvent was removed under vacuum, and 81.7 mg of (2-morpholinyl-2-oxoethyl)carbamic acid tert-butyl ester 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-morpholinyl-2-oxyethyl)carbamic acid tert-butyl ester is as follows Fig. 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] Embodiment 11

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

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

[0135] The NMR spectrum of the product N-butyl-4-(morpholine-4-carbonyl)-N-propylbenzenesulfonamide is as follows Fig. 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-Phenylbenzoic acid (99.0 mg, 1 equiv.) and Ir[dF(CF3)ppy]2(dtbbpy)PF6 (2.8 mg) were added to a 12 mL headspace glass vial with a PTFE gasket, and then evacuated and an SF6 balloon was inserted. Then 3.0 mL of anhydrous acetonitrile was added and bubbled for 3 minutes. Then n-butylamine (494.2 μL, 10 equiv.) and N,N-diisopropylethylamine (434.6 μL, 5 equiv.) were added, and the reaction system was placed under a 15 W, 465 nm blue LED light source and stirred for 20 hours. After the reaction was completed, the organic solvent was removed under vacuum, and 8.9 mg of N-butyl-[1,1'-biphenyl]-4-carboxamide was obtained by silica gel column chromatography (petroleum ether: ethyl acetate volume ratio = 5:1), with a yield of 7%.

[0139] The NMR spectrum of the product N-butyl-[1,1'-biphenyl]-4-carboxamide is as follows Fig.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 equiv.) and Ir[dF(CF3)ppy]2(dtbbpy)PF6 (2.8 mg) were added to a 12 mL headspace glass vial with a PTFE gasket, and then evacuated and an SF6 balloon was inserted. Then 3.0 mL of anhydrous acetonitrile was added and bubbled for 3 minutes. Subsequently, diethylamine (517.3 μL, 10 equiv.) and N,N-diisopropylethylamine (434.6 μL, 5 equiv.) were added, and the reaction system was placed under a 15 W, 465 nm blue LED light source and stirred for 20 hours. After the reaction was completed, the organic solvent was removed under vacuum, and 64.9 mg of N,N-diethyl-3-methylbenzamide was obtained by silica gel column chromatography (petroleum ether: ethyl acetate volume ratio = 3:1), with a yield of 68%.

[0143] The NMR spectrum of the product N, N-diethyl-3-methylbenzamide is as follows Fig.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] Embodiment 14

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

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

[0147] The NMR spectrum of the product N, N-diethyl-2-(naphthalen-1-yloxy)propionamide is as follows Fig.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] Embodiment 15

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

[0150] 2,3-Dihydro-1,4-benzodioxane-6-carboxylic acid (90.1 mg, 1 equiv.) and Ir[dF(CF3)ppy]2(dtbbpy)PF6 (2.8 mg) were added to a 12 mL headspace glass vial with a PTFE gasket, and then evacuated and an SF6 balloon was inserted. Then 3.0 mL of anhydrous acetonitrile was added and bubbled for 3 minutes. Subsequently, hexahydropyridine (493.9 μL, 10 equiv.) and N,N-diisopropylethylamine (434.6 μL, 5 equiv.) were added, and the reaction system was placed under a 15 W, 465 nm blue LED light source and stirred for 20 hours. After the reaction was completed, 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 as follows Fig.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-butyloxycarbonyl)glyceryl-L-proline methyl ester

[0154] (tert-Butyloxycarbonyl)glycine (87.5 mg, 1 equiv.), L-proline methyl ester (645.4 mg, 10 equiv.), Ir[dF(CF3)ppy]2(dtbbpy)PF6 (2.8 mg) were added to a 12 mL headspace glass vial with a PTFE gasket, and then evacuated and an SF6 balloon was inserted, and then 3.0 mL of anhydrous acetonitrile was added and bubbled for 3 minutes. Subsequently, N,N-diisopropylethylamine (434.6 μL, 5 equiv.) was added, and the reaction system was placed under a 15 W, 465 nm blue LED light source and stirred for 20 hours. After the reaction was completed, the organic solvent was removed under vacuum, and 249.0 mg of (tert-Butyloxycarbonyl)glyceryl-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)glyceryl-L-proline methyl ester is as follows Fig.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-mentioned embodiment, the irradiation is performed at room temperature under SF6 gas at one atmosphere pressure.

[0159] As can be seen from Examples 1-16, the present invention uses easily available carboxylic acids and amine compounds as reaction substrates, commercially available Ir[dF(CF3)ppy]2(dtbbpy)PF6 as a photocatalyst, and cheap and easily available N,N-diisopropylethylamine as a base. Under an atmospheric pressure of SF6 gas, at room temperature, 15W of 465nm blue light is used as a light source to simply and efficiently synthesize amide compounds. The method has good tolerance to aromatic, heteroaryl carboxylic acids, aliphatic carboxylic acids, and amino acids, and different amine compounds have good reactivity. There are no particularly strict restrictions on the number and type of substituents in carboxylic acids and amine compounds, and the synthesis method is applied to the synthesis of amide drugs, and DEET, fenpropamide, and CX546 are successfully obtained. Therefore, it is a general synthesis method for amide compounds with mild conditions, simple operation, and easy industrial promotion. And the method effectively activates and utilizes SF6, a greenhouse gas, and makes full use of SF6 decomposition products to realize the amidation reaction of carboxylic acids, turning SF6 into treasure.

[0160] Comparative Example 1

[0161] According to the method of Example 12, the reaction conditions were changed. The changed conditions and yield results are shown in the following table:

[0162]

[0163] Serial number Amine compounds <![CDATA[SF6]]> Solvents 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 for 20 hours.

[0165] The above embodiments are only used to illustrate the technical solutions of the present invention, rather than to limit the same. Although the present invention has been described in detail with reference to the aforementioned embodiments, those skilled in the art should understand that the technical solutions described in the aforementioned embodiments may still be modified, or some of the technical features may be replaced by equivalents. However, these modifications or replacements do not deviate the essence of the corresponding technical solutions from the spirit and scope of the technical solutions of the embodiments of the present invention.

Claims

1. A method for carboxylic acid amidation, characterized in that: The method uses amine compounds and carboxylic acid compounds as raw materials and an organic solvent as solvent, and irradiates the mixture with light in the presence of a photocatalyst, a base and sulfur hexafluoride, and reacts in the organic solvent to obtain amide compounds; wherein the organic solvent is a mixture of one or more of tetrahydrofuran, acetonitrile and dichloromethane; and the amine compound is a secondary amine.

2. The method for carboxylic acid amidation according to claim 1, characterized in that: The structural formula of the secondary amine is Wherein, R1 and R2 are both alkyl and substituted alkyl.

3. The method for carboxylic acid amidation according to claim 1, characterized in that: The secondary amine is one of morpholine, diethylamine, piperidine and L-proline methyl ester.

4. The method for carboxylic acid amidation according to claim 1, characterized in that: The structural formula of the carboxylic acid compound is Wherein, R is one of aryl, substituted aryl, alkyl, substituted alkyl, and substituted alkenyl.

5. The method for carboxylic acid amidation according to claim 4, characterized in that: The substituents in the substituted alkyl, substituted aryl and substituted alkenyl are all selected from C1-C 20 Alkyl, C2-C 20 Alkenyl, C6-C 20 Aryl, 5-10 membered heteroaryl containing 1-3 heteroatoms of one or more of O, N, S, C2-C 30 Ester group, C3-C 20 and containing 1 to 5 cycloalkyl, trifluoromethyl, halogen, methoxy, dimethylamino, biphenyl, One or more of .

6. The method for carboxylic acid amidation according to claim 1, characterized in that: 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-butyloxycarbonyl)glycine.

7. The method for carboxylic acid amidation according to claim 1, characterized in that: The organic solvent is acetonitrile.

8. The method for carboxylic acid amidation according to claim 1, characterized in that: The photocatalyst is a mixture of one or more organic photocatalysts or transition metal photocatalysts.

9. The method for carboxylic acid amidation according to claim 8, characterized in that: The organic photocatalyst is 4CZIPN, Mes-Acr + ClO4 — One or a mixture of two.

10. The method for carboxylic acid amidation according to claim 8, characterized in that: The transition metal photocatalyst is one of Ir[dF(CF3)ppy]2(dtbbpy)PF6 and Ir(dtbbpy)ppy2PF6 or a mixture of the two.

11. The method for carboxylic acid amidation according to claim 10, characterized in that: The photocatalyst is Ir[dF(CF3)ppy]2(dtbbpy)PF6.

12. The method for carboxylic acid amidation according to claim 1, characterized in that: The base is an organic base.

13. The method for carboxylic acid amidation according to claim 12, characterized in that: The organic base is N,N-diisopropylethylamine.

14. The method for carboxylic acid amidation according to claim 1, characterized in that: The molar ratio of the amine compound to the carboxylic acid compound is 1:1 to 20:

1.

15. The method for carboxylic acid amidation according to claim 14, characterized in that: The molar ratio of the amine compound to the carboxylic acid compound is 10:

1.

16. The method for carboxylic acid amidation according to claim 1, characterized in that: The molar ratio of the carboxylic acid compound to the photocatalyst is 100:0.2-1.

17. The method for carboxylic acid amidation according to claim 16, characterized in that: The molar ratio of the carboxylic acid compound to the photocatalyst is 100:0.

5.

18. The method for carboxylic acid amidation according to claim 1, characterized in that: The molar ratio of the carboxylic acid compound to the base is 1:1-1:

10.

19. The method for carboxylic acid amidation according to claim 18, characterized in that: The molar ratio of the carboxylic acid compound to the base is 1:

5.

20. The method for amidation of carboxylic acid according to claim 1, characterized in that: During the illumination process, blue light with a wavelength of 450-480nm was used as the light source.

21. The method for amidation of carboxylic acid according to claim 1, characterized in that: During the illumination process, the SF6 gas pressure is 1atm.

22. The method for amidation of carboxylic acid according to claim 1, characterized in that: During the illumination process, the reaction temperature is 0-50°C and the reaction time is 5-48h.

23. The method for amidation of carboxylic acid according to claim 22, characterized in that: During the illumination process, the reaction temperature was room temperature and the reaction time was 20 h.

24. The method for amidation of carboxylic acid according to any one of claims 1 to 23, characterized in that: The usage ratio of the carboxylic acid compound and the solvent is 0.5-0.1 mmol:1 mL.

25. An amide compound, characterized in that: The method is prepared by the carboxylic acid amidation method as described in any one of claims 1 to 24.

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