Method for constructing amide compound from nitro-aromatic hydrocarbon and olefin under light induction

Abstract

The invention belongs to the technical field of synthesis of organic compounds, and relates to a synthesis method of an amide compound in a photochemical environment. According to the method, nitro-aromatic hydrocarbon and olefin are taken as raw materials and react in an acetonitrile solvent for 48 hours under the light condition of 390 nm, so that direct construction of various amide compounds is realized. Free radical addition of nitro-aromatic hydrocarbon to olefin is initiated through optical excitation, and through an intramolecular synergistic cyclization-cracking-rearrangement process of an N-O = C dipole intermediate, cascade cracking of olefin and insertion of nitrogen atoms are realized in a one-pot system, and an amide skeleton is efficiently constructed. The method is wide in raw material source, simple and convenient to operate, mild in condition, safe and efficient, and has a remarkable economic value and a good industrial application prospect.

Description

TECHNICAL FIELD

[0001] The application belongs to the technical field of organic compound synthesis, and relates to a synthesis method of an amide compound in a photochemical environment. BACKGROUND

[0002] N-heterocyclic skeleton is a basic structural unit in medicinal chemistry, and it is of great significance to develop a general strategy that can adapt to the demand of diversified synthesis. In recent years, skeleton editing based on nitrogen insertion has become an important way to construct this type of structure. From the reaction mechanism, the existing methods can be mainly divided into two categories: one type relies on the rearrangement of pre-functionalized intermediates (such as Littig-like intermediates) to achieve nitrogen insertion; the other type uses highly active nitrene species (such as free nitrene, metal nitrene or nitrogen ion) to insert into unsaturated bonds through a synergistic process.

[0003] In the nitrogen insertion of C(sp 2 )=C(sp 2 ) bond (such as aromatic hydrocarbon and olefin), the nitrene strategy has been widely used in the synthesis of nitrogen heteroaromatics; while in the construction of N-heterocyclic containing amide structure (such as amide structure), the strategy based on the rearrangement of specific intermediates still plays an irreplaceable role in the nitrogen insertion of C(sp 3 )-C(sp 3 ) bond. At present, the synthesis method of amide structure is relatively mature, covering various paths such as transition metal-catalyzed amine carbonylation, aldehyde imine oxidation, Beckmann / Schmidt rearrangement, Paserini / Ugi reaction and enzyme catalysis. However, it is still a promising research direction to develop an efficient and green synthesis path to construct structurally diverse amide skeleton by breaking C(sp 2 )=C(sp 2 ) and C(sp 3 )-C(sp 3 ) bonds and realizing nitrogen insertion.

[0004] On the other hand, nitroarene has been widely concerned as a multifunctional reagent in synthetic chemistry due to its unique photochemical properties in recent years, involving hydrogen atom transfer (HAT), oxygen atom transfer (OAT), electron donor-acceptor (EDA) complex and other mechanisms. Among them, the oxidative cleavage of olefins by photoexcited nitroarene has been successfully applied to the synthesis of carbonyl compounds, and the reaction is usually based on the cycloaddition-cleavage mechanism of N-O=C dipole. It is worth noting that the application of N-O=C dipole in dipolar cycloaddition reaction is not widespread, and at present it is mainly limited to [3+2] cycloaddition reaction. Therefore, it is of certain value to realize the skeleton editing of a series of amide compounds by using the rearrangement of N-O=C dipole generated by photoexcited nitroarene to form a more stable structure.

[0005] Based on the above background, the present application uses nitroarene as a nitrogen atom insertion reagent to edit the skeleton of olefins under photochemical conditions to construct amide compounds. Compared with traditional methods, the present strategy is mild, environmentally friendly, and has strong substrate adaptability, showing good application prospects for drug synthesis and providing a new way for efficient construction of amide structural units. SUMMARY

[0006] The present application uses a photo reaction mode and uses nitroarene as a nitrogen atom insertion reagent to edit the skeleton of olefins. The process includes radical addition of photo-excited nitroarene to olefins, and intramolecular concerted cyclization-cleavage-rearrangement of N-O=C dipole intermediates, thereby realizing cascade cleavage of C(sp 2 )=C(sp 2 ) and C(sp 3 )-C(sp 3 ) bonds and nitrogen atom insertion, providing a novel synthetic method for the preparation of amide compounds.

[0007] To achieve the above object, the method uses light to irradiate nitroarene, so that the electrons jump from the ground state to the excited state, and then sequentially react with olefins through a radical addition reaction and a dipole ring cleavage to produce N-O=C dipole intermediates, and then intramolecular concerted cyclization-cleavage-rearrangement of N-O=C dipole intermediates constructs a series of amide compounds.

[0008] As a preferred mode of the present application, the reaction equation for synthesizing amide compounds is:

[0009]

[0010] In formula (1), R 1 is selected from any one of phenyl, pyridine or phenyl connected with an electron-deficient substituent; in formula (2), R 2 is selected from any one of methyl or phenyl, and R 3 is selected from any one of methyl, phenyl or pyridine.

[0011] The synthesis process of the compound shown in formula (3) is: dissolving the compound shown in formula (1) (2) in a solvent, and reacting under light conditions to generate the compound shown in formula (3);

[0012] The solvent is acetonitrile, the wavelength range of light is 390 nm, the reaction temperature is 25℃, and the reaction time is 48 h.

[0013] In the reaction system, the molar ratio of the compound shown in formula (1) to the compound shown in formula (2) is 1: (1-3).

[0014] The present application has the following advantages in synthesizing amide compounds:

[0015] (1) The present application efficiently constructs a series of amide compounds by radical cycloaddition and dipole cleavage of nitroarene and olefin to generate N-O=C dipole, followed by synergistic isomerization rearrangement of the intermediate under mild photochemical conditions. This strategy provides a green and efficient synthetic method for editing amide skeleton.

[0016] (2) The raw materials used in the present application, nitroarene and olefin, are inexpensive and easy to obtain, and the operation is simple without heating, which effectively reduces the synthesis cost and is beneficial to industrial production.

[0017] (3) The synthesis method of the present application has wide substrate applicability and can be compatible with various common functional groups, natural product and drug molecular skeletons. DETAILED DESCRIPTION

[0018] The technical solutions in the embodiments of the present application will be described below in a clear and complete manner. Obviously, the described embodiments are only a part of the embodiments of the present application, rather than all the embodiments. Based on the embodiments in the present application, all other embodiments obtained by those skilled in the art without creative labor fall within the scope of protection of the present application.

[0019] In this embodiment, N-(2,6-difluorophenyl)-N-methylbenzamide (3a) is synthesized by the reaction of 1,3-difluoro-2-nitrobenzene (1a) and prop-1-en-2-ylbenzene (2a):

[0020] The reaction equation is:

[0021]

[0022] The synthesis steps and processes are as follows: 1a (0.2 mmol, 31.8 mg) and 2a (0.3 mmol, 35.4 mg) are added to a 10 mL reaction tube equipped with a magnetic stirrer, and then 5.0 mL of acetonitrile is added. Under an air atmosphere, the reaction tube is fixed on a magnetic stirrer and irradiated at 390 nm for 48 hours. After dilution with 5 mL of ethyl acetate, the solvent is removed by rotary evaporation under reduced pressure. The crude product is separated and purified by column chromatography (petroleum ether: ethyl acetate = 10:1) to obtain the target product 3a (25.2 mg) with a yield of 51%.

[0023] The nuclear magnetic resonance data of compound (3a) are as follows:

[0024] 1H NMR (400 MHz, DMSO) δ 7.36 - 7.29 (m, 2H), 7.25 (d, J = 4.4 Hz, 4H), 7.09 (t, J = 8.3 Hz, 2H), 3.27 (s, 3H).

[0025] 13 C NMR (101 MHz, DMSO) δ 170.9, 158.0 (dd, J = 249.1, 4.2 Hz), 135.5, 130.74, 130.6 (t, J = 10.1 Hz), 128.4, 127.2, 121.8 (t, J = 16.0 Hz), 112.8 (dd, J = 18.4, 4.9 Hz), 36.5.

[0026] 19 F NMR (376 MHz, DMSO) δ -119.8.

[0027] In this example, N-(2,6-difluorophenyl)-N-methylisonicotinamide (3a) was synthesized by reacting 1,3-difluoro-2-nitrobenzene (1a) with 4-(prop-1-en-2-yl)pyridine (2b):

[0028]

[0029] The reaction equation is:

[0030]

[0031] The synthesis steps and procedures are: into a 10 mL reaction tube equipped with a magnetic stirrer, 1a (0.2 mmol, 31.8 mg), 2b (0.3 mmol, 35.7 mg) were added, and then 5.0 mL of acetonitrile was added; under air atmosphere, the reaction tube was fixed on the magnetic stirrer, and reacted under 390 nm light irradiation for 48 hours, diluted with 5 ml of ethyl acetate, and the solvent was removed by rotary evaporation under reduced pressure. The crude product was separated and purified by column chromatography (petroleum ether: ethyl acetate = 1:1) to obtain the target product 3b (25.3 mg), with a yield of 46%.

[0032] The nuclear magnetic resonance data of compound (3b) are:

[0033] 1 H NMR (400 MHz, CDCl3) δ 7.38 - 7.29 (m, 2H), 7.01 (d, J = 3.2 Hz, 1H), 6.97 (t, J = 8.0 Hz, 2H), 6.82 (t, J = 4.2 Hz, 1H), 3.36 (s, 3H).

[0034] ​13 C NMR (101 MHz, CDC13) δ 163.4, 159.2 (dd, J = 252.7, 3.8 Hz), 136.6, 131.3, 130.4, 129.9 (t, J = 9.9 Hz), 126.8, 121.5, 112.5 (d, J = 23.4 Hz), 37.1.

[0035] 19 F NMR (376 MHz, CDC13) δ -118.7.

[0036] Example 3: In this example, N-(2,6-difluorophenyl)-N-methylacetamide (3c) was synthesized by reacting 1,3-difluoro-2-nitrobenzene (la) with 2-methylprop-l-ene (2c):

[0037] The reaction equation is:

[0038]

[0039] The synthesis procedure and process were as follows: into a 10 mL reaction tube equipped with magnetic stirring, la (0.2 mmol, 31.8 mg), 2c (0.9 mmol, 50.4 mg) were added, then 5.0 mL acetonitrile was added; under air atmosphere, the reaction tube was fixed on the magnetic stirrer, and reacted under 390 nm light irradiation for 48 hours, diluted with 5 ml ethyl acetate, and the solvent was removed by rotary evaporation under reduced pressure. The crude product was separated and purified by column chromatography (petroleum ether: ethyl acetate = 20: 1) to obtain the target product 3c (19.6 mg), with a yield of 53%.

[0040] The nuclear magnetic resonance data of compound (3c) were as follows:

[0041] 1 H NMR (400 MHz, CDC13) δ 7.39 - 7.27 (m, 1H), 7.00 (dd, J = 8.3, 7.4 Hz, 2H), 3.18 (s, 3H), 1.86 (s, 3H).

[0042] 13 C NMR (101 MHz, CDC13) δ 170.8, 158.8 (dd, J = 252.0, 4.2 Hz), 129.5 (t, J = 9.8 Hz), 121.2 (t, J = 16.6 Hz), 112.4 (dd, J = 18.7, 5.2 Hz), 35.5, 21.2.

[0043] 19FNMR (376 MHz, CDCI3) δ -118.8.

[0044] In this example, N,N-diphenylbenzamide (3d) was synthesized by the reaction of Nitrobenzene (Id) and ethene-1,1 -d iyldibenzene (2d):

[0045] The reaction equation is:

[0046]

[0047] The synthesis procedure and process are: into a 10 mL reaction tube equipped with magnetic stirring, 1d (0.2 mmol, mg), 2d (0.3 mmol, 54.0 mg) were added, then 5.0 mL acetonitrile was added; under air atmosphere, the reaction was fixed on the magnetic stirrer, and reacted under 390 nm light irradiation for 48 hours, diluted with 5 ml ethyl acetate, and the solvent was removed by rotary evaporation under reduced pressure. The crude product was separated and purified by column chromatography (petroleum ether: ethyl acetate = 10: 1) to obtain the target product 3d (16.4 mg), with a yield of 30%.

[0048] The nuclear magnetic resonance data of compound (3d) are:

[0049] 1 H NMR (400 MHz, CDCI3) δ 7.49 - 7.44 (m, 2H), 7.32 - 7.27 (m, 5H), 7.24 - 7.13 (m, 8H).

[0050] 13 C NMR (101 MHz, CDCI3) δ 170.6, 143.9, 136.1, 130.2, 129.2, 129.1, 127.9, 127.5, 126.3. In this example, N-phenyl-N-(pyridin-4-yl)benzamide (3e) was synthesized by the reaction of 4-Nitropyridine (1e) and ethene-1,1 -d iyldibenzene (2d):

[0051] The reaction equation is:

[0052]

[0053] The synthetic procedure and process was: to a 10 mL reaction tube equipped with a magnetic stir bar was added 1e (0.2 mmol, 24.8 mg), 2d (0.3 mmol, 54.0 mg), and 5.0 mL of acetonitrile; the reaction was fixed on a magnetic stirrer under air atmosphere, and irradiated at 390 nm for 48 h, diluted with 5 mL of ethyl acetate, and the solvent was removed by rotary evaporation under reduced pressure. The crude product was separated and purified by column chromatography (petroleum ether: ethyl acetate = 10: 1) to give the target product 3e (29.0 mg) in 53% yield.

[0054] The NMR data of compound (3e) was:

[0055] 1 H NMR (400 MHz, CDC13) δ 8.42 (d, J = 5.5 Hz, 2H), 7.43 - 7.35 (m, 2H), 7.29 - 7.20 (m, 3H), 7.17 - 7.10 (m, 3H), 7.04 (dd, J = 5.4, 3.4 Hz, 2H), 6.99 (dd, J = 4.8, 1.4 Hz, 2H).

[0056] 13 C NMR (101 MHz, CDC13) δ 170.7, 150.9, 150.6, 142.4, 135.3, 130.9, 129.7, 129.1, 128.5, 128.1, 127.5, 120.1.

[0057] In this example, N-(4-cyanophenyl)-N-phenylbenzamide (3f) was synthesized by the reaction of 4-Nitrobenzonitrile (1f) and ethene-1,1-diyldibenzene (2d):

[0058] The reaction equation was:

[0059]

[0060] The synthetic procedure and process was: to a 10 mL reaction tube equipped with a magnetic stir bar was added 1f (0.2 mmol, 29.6 mg), 2d (0.3 mmol, 54.0 mg), and 5.0 mL of acetonitrile; the reaction was fixed on a magnetic stirrer under air atmosphere, and irradiated at 390 nm for 48 h, diluted with 5 mL of ethyl acetate, and the solvent was removed by rotary evaporation under reduced pressure. The crude product was separated and purified by column chromatography (petroleum ether: ethyl acetate = 10: 1) to give the target product 3f (31.0 mg) in 52% yield.

[0061] The NMR data of compound (3f) was:

[0062] 1 H NMR (600 MHz, DMSO) δ 7.81 (d, J = 8.6 Hz, 2H), 7.48 - 7.42 (m, 2H), 7.36 (ddd, J = 17.7, 9.9, 4.9 Hz, 5H), 7.28 (t, J = 7.6 Hz, 2H), 7.25 (dd, J = 9.1, 8.0 Hz, 3H).

[0063] 13 C NMR (151 MHz, DMSO) δ 170.3, 148.2, 143.2, 136.2, 133.6, 130.8, 129.9, 129.2, 128.9, 128.4, 128.1, 127.7, 119.0, 108.7.

[0064] Example 7: In this example, N-(4-acetylphenyl)-N-phenylbenzamide (3g) was synthesized by reacting 4-Nitroacetophenone (1g) with ethene-1,1-diyldibenzene (2d):

[0065] The reaction equation is:

[0066]

[0067] The synthesis steps and procedures are: into a 10 mL reaction tube equipped with a magnetic stirrer, 1 g (0.2 mmol, 33.0 mg), 2d (0.3 mmol, 54.0 mg) was added, and then 5.0 mL of acetonitrile was added; under air atmosphere, the reaction was fixed on a magnetic stirrer, and reacted under 390 nm light irradiation for 48 hours, diluted with 5 ml of ethyl acetate, and the solvent was removed by rotary evaporation under reduced pressure. The crude product was separated and purified by column chromatography (petroleum ether: ethyl acetate = 10: 1) to obtain the target product 3g (24.5 mg), with a yield of 39%.

[0068] The nuclear magnetic resonance data of compound (3g) is:

[0069] 1 H NMR (400 MHz, CDCl3) δ 7.89 (d, J = 8.6 Hz, 2H), 7.50 - 7.44 (m, 2H), 7.41 - 7.35 (m, 2H), 7.34 - 7.28 (m, 3H), 7.25 - 7.19 (m, 3H), 7.14 - 7.07 (m, 2H), 7.14 - 7.07 (m, 3H).

[0070] 13C NMR (101 MHz, CDC13) δ 197.0, 170.7, 148.2, 143.3, 135.6, 134.4, 130.6, 129.4, 129.3, 129.2, 128.4, 128.1, 127.0, 126.7, 26.6.

[0071] Example 8: In this example, ethyl 4-(N-phenylbenzamido)benzoate (3h) was synthesized by reacting ethyl p-nitrobenzoate (1h) with ethene-1,1-diyldibenzene (2d):

[0072] The reaction equation is:

[0073]

[0074] The synthesis procedure was as follows: into a 10 mL reaction tube with magnetic stirring, 1h (0.2 mmol, 39.1 mg), 2d (0.3 mmol, 54.0 mg) were added, then 5.0 mL acetonitrile was added; under air atmosphere, the reaction was fixed on a magnetic stirrer, and reacted under 390 nm light irradiation for 48 hours, diluted with 5 ml ethyl acetate, and the solvent was removed by rotary evaporation under reduced pressure. The crude product was separated and purified by column chromatography (petroleum ether: ethyl acetate = 10: 1) to obtain the target product 3h (28.3 mg), with a yield of 41%.

[0075] The nuclear magnetic resonance data of compound (3h) were as follows:

[0076] 1 H NMR (400 MHz, CDC13) δ 7.91-7.85 (m, 2H), 7.42-7.35 (m, 2H), 7.23 (ddd, J = 5.2, 4.6, 2.3 Hz, 3H), 7.17-7.10 (m, 5H), 7.08-7.02 (m, 2H), 4.28 (q, J = 7.1 Hz, 2H), 1.30 (t, J = 7.1 Hz, 3H).

[0077] 13 C NMR (101 MHz, CDC13) δ 170.7, 165.9, 148.0, 143.4, 135.7, 130.6, 130.4, 129.4, 129.2, 128.0, 127.9, 127.8, 126.9, 126.7, 61.1, 14.3.

[0078] Example 9: In this example, N-(3,5-bis(trifluoromethyl)phenyl)-N- phenylbenzamide (3i) was synthesized by reacting 3,5-Bis(trifluoromethyl)nitrobenzene (li) with ethene-1,1 -d iyldibenzene (2d):

[0079] The reaction equation is:

[0080]

[0081] The synthesis procedure was as follows: into a 10 mL reaction tube with magnetic stirring, li (0.2 mmol, 51.8 mg), 2d (0.3 mmol, 54.0 mg) were added, then 5.0 mL acetonitrile was added; under air atmosphere, the reaction was fixed on a magnetic stirrer, and reacted for 48 h under 390 nm light irradiation, diluted with 5 ml ethyl acetate, and the solvent was removed by rotary evaporation under reduced pressure. The crude product was separated and purified by column chromatography (petroleum ether: ethyl acetate = 10: 1) to obtain the target product 3i (28.8 mg), with a yield of 50%.

[0082] The NMR data of compound (3i) were as follows:

[0083] 1 H NMR (600 MHz, CDCI3) δ 7.60 (s, 1 H), 7.56 (s, 2H), 7.35 (d, J = 7.2 Hz, 2H), 7.27 - 7.16 (m, 3H), 7.16 - 7.11 (m, 3H), 6.99 (d, J = 7.5 Hz, 2H).

[0084] 13 C NMR (151 MHz, CDCI3) δ 170.8, 145.3, 142.6, 134.9, 132.4 (q, J = 33.7 Hz), 131.0, 129.8, 129.2, 128.1 (d, J = 5.2 Hz), 127.6, 126.6 (d, J = 3.0 Hz), 123.8, 122.0, 119.9 - 118.9 (m).

[0085] 19 F NMR (565 MHz, CDCI3) δ -63.0.

[0086] Example 10: In this example, N-(4-chlorophenyl)-N-phenylbenzamide (3j) was synthesized by the reaction of 4-Chloronitrobenzene (1j) with ethene-1,1-diyldibenzene (2d):

[0087] The reaction equation is:

[0088]

[0089] The synthesis steps and procedures are: into a 10 mL reaction tube equipped with magnetic stirring, 1j (0.2 mmol, 31.5 mg), 2d (0.3 mmol, 54.0 mg) were added, and then 5.0 mL of acetonitrile was added; under air atmosphere, the reaction was fixed on a magnetic stirrer, and reacted under 390 nm light irradiation for 48 hours, diluted with 5 ml of ethyl acetate, and the solvent was removed by rotary evaporation under reduced pressure. The crude product was separated and purified by column chromatography (petroleum ether: ethyl acetate = 10:1) to obtain the target product 3j (25.8 mg), with a yield of 42%.

[0090] The nuclear magnetic resonance data of compound (3j) are:

[0091] 1 H NMR (400 MHz, CDCl3) δ 7.39-7.32 (m, 2H), 7.22-7.05 (m, 8H), 7.04-6.94 (m, 4H).

[0092] 13 C NMR (101 MHz, CDCl3) δ 170.6, 143.6, 142.5, 135.8, 131.9, 130.4, 129.3, 129.3, 129.2, 128.5, 128.0, 127.6, 126.7.

[0093] The present application successfully constructs a series of amide compounds by the radical cycloaddition and dipole cleavage of nitroarene and olefin under light excitation, and further through the synergistic isomerization rearrangement process of N-O=C dipole. This strategy realizes efficient editing of amide skeleton under mild and photochemical conditions without heating, and provides a green and efficient synthetic method. The raw materials of nitroarene and olefin used are cheap and easy to obtain, the operation is simple, and the synthesis cost is significantly reduced, which has good potential for industrial application. In addition, this method has wide substrate applicability, can be compatible with various common functional groups, and is suitable for the derivatization and modification of natural product and drug molecule skeleton.

Claims

1. A method for synthesizing an amide compound, characterized in that, In acetonitrile solvent and under 390 nm light irradiation, nitroaromatic hydrocarbons were used as nitrogen atom insertion reagents to edit the skeleton of olefins, thereby achieving the synthesis of amide compounds.

2. The method for synthesizing amide compounds according to claim 1, characterized in that, The reaction equation is: In equation (1), R 1 For phenyl, pyridine, or phenyl with an electron-deficient substituent, in formula (2), R 2 It is methyl or phenyl, R 3 It can be methyl, phenyl, or pyridine; The synthesis process of the compound shown in formula (3) is as follows: the compounds shown in formula (1) and (2) are dissolved in a solvent and reacted under light to generate the compound shown in formula (3); The solvent is acetonitrile, the light wavelength range is 390 nm, the reaction temperature is 25 °C, and the reaction time is 48 h. In the reaction system, the molar ratio of the compound shown in formula (1) and the compound shown in formula (2) is 1:(1-3).

3. The method for synthesizing amide compounds according to claims 1 and 2, characterized in that: In equation (1) and R 1 Selected from phenyl, pyridine, or phenyl with an electron-deficient substituent, wherein the electron-deficient substituent includes cyano, ethyl ester, acetyl, trifluoromethyl, or halogen; in formula (2), R 2 Selected from either methyl or phenyl, R 3 It is selected from any one of methyl, phenyl, or pyridine.

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