Selective controllable synthesis method of two alkyl arylamine compounds

Abstract

The invention belongs to the technical field of chemical synthesis, and particularly relates to a selective controllable synthesis method of two alkyl arylamine compounds. The synthesis method comprises the following steps: S1, mixing nitro-aromatic hydrocarbon with aryl aldehyde / ketone or alkyl aldehyde / ketone, and then adding copper salt, nested carborane and an organic solvent to obtain a mixture; s2, irradiating the mixture with blue light at 25-80 DEG C under the protection of inert gas to obtain a product; s3, after the reaction is finished, separating and purifying a product to obtain an N-monoalkyl arylamine compound or an N-dialkyl arylamine compound; the feeding molar ratio of the nitro-aromatic hydrocarbon to the aryl aldehyde / ketone or alkyl aldehyde / ketone to the copper salt to the nested carborane is 10: (12-24): 1: 5; the molar concentration of the nitro-aromatic hydrocarbon in the organic solvent is 0.25 M.

Description

Technical Field

[0001] The invention belongs to the technical field of chemical synthesis, and in particular relates to a selective and controllable synthesis method of two types of alkyl aromatic amine compounds. Background Art

[0002] Alkyl aryl amine compounds are important intermediates in organic synthesis and have a wide range of application values ​​in the fields of medicine, materials, military, agriculture, etc. The structure of alkyl aryl amine can be found in many drugs. For example, selexipag for the treatment of patients with pulmonary hypertension; astemizole, a marketed drug for the treatment of rhinitis, conjunctivitis and chronic urticaria; and the kinase inhibitor rituximab, a biologically active drug. At present, the synthesis of alkyl aryl amine compounds has been well improved and developed in the past few decades, including the reductive amination reaction of aromatic aldehydes and ketones with aromatic amines, the palladium-catalyzed Buchwald-Hartwig coupling reaction, and the coupling reaction of alkyl halides with nitrogen-containing compounds. Although the reductive amination method of aldehydes and ketones with aromatic amines can efficiently synthesize alkyl aryl amines, the feed ratio of amine substrate to carbonyl substrate requires harsh anhydrous reaction conditions to prevent excessive alkylation or side reactions of hydrolysis of imine intermediates. In addition, this method relies on the pre-functionalization and activation of the substrate, which invisibly greatly increases the synthesis steps and synthesis costs, and also causes waste of raw materials and pollution to the environment. Summary of the invention

[0003] In view of the shortcomings of existing technologies, we have developed a mild photoinduced copper-catalyzed reaction system, using nitroaromatic compounds and aldehydes and ketones as primary reaction raw materials, and for the first time using multifunctional nested carborane as a copper ligand and reducing agent. It is worth mentioning that nested carborane, as a three-dimensional BH cage, is milder and more reaction-regulatory than traditional borane complexes and borohydrides, as well as having excellent functional group compatibility, and has the function of selectively and controllably synthesizing N-monoalkylated or N-dialkylated products.

[0004] The purpose of the present invention can be achieved through the following technical solutions:

[0005] A selective and controllable synthesis method of two types of alkyl aromatic amine compounds, the synthesis method comprising the following steps:

[0006] S1, mixing nitroaromatic hydrocarbon with aromatic aldehyde / ketone or alkyl aldehyde / ketone, and then adding copper salt, nested carborane and organic solvent to obtain a mixture;

[0007] S2, irradiating the mixture with blue light at 25°C-80°C under inert gas protection to obtain a product;

[0008] S3. After the reaction is completed, the product is separated and purified to obtain an N-monoalkyl aromatic amine compound or an N-dialkyl aromatic amine compound;

[0009] The molar ratio of the nitroaromatic hydrocarbon, aromatic aldehyde / ketone or alkyl aldehyde / ketone, copper salt and nested carborane is 10:(12-24):1:5; the molar concentration of the nitroaromatic hydrocarbon in the organic solvent is 0.25M;

[0010] The reaction formula is:

[0011]

[0012] Ar is one of benzene, naphthalene, phenanthrene, pyrazine, pyridazine, benzofuran, benzothiazole, 1,2-benzopyrone, indole, quinoline, and isoquinoline;

[0013] The R 1 ~R 5 One or more selected from H, F, Cl, Br, I, NH2, -CN, -CHO, -Bpin, C1-C10 alkyl, C2-C10 alkenyl, C3-C10 alkynyl, C1-C10 alkoxy, phenylethynyl, cyclopropane, halogenated alkyl, cyclohexenyl, benzaldehyde, tetraphenylethylene, ethyl acetate, isobutylamide;

[0014] R 6 , R 7 One or two selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, trihalomethyl;

[0015] As a preferred embodiment of the present invention, the aryl group is phenyl, thiophene, furan, pyrrole, pyrazole or pyridine substituted by one or more of H, F, Cl, Br, I, -CHO, C1-C10 alkoxy, C3-C10 alkoxycarbonyl, C2-C10 alkenyl, and phenyl.

[0016] As a preferred embodiment of the present invention, the copper salt reagent is selected from cuprous iodide, cuprous bromide, cuprous chloride, cuprous chloride, cuprous thiocyanate, tetraacetonitrile copper hexafluorophosphate, cupric bromide, cupric chloride, cupric acetate, and cupric trifluorosulfonate.

[0017] As a preferred embodiment of the present invention, the nested carborane is one of nido-CB1, nido-CB2, nido-CB3 or nido-CB4.

[0018] As a preferred embodiment of the present invention, the organic solvent is selected from one or more of dichloromethane, dichloroethane, acetonitrile, methanol, ethanol, tetrahydrofuran, tert-butanol, ethylene glycol dimethyl ether, ethyl acetate, and 1,4-dioxane.

[0019] As a preferred solution of the present invention, the wavelength of the blue light is 395nm-400nm; and the irradiation time is 3-14 hours.

[0020] An alkyl aromatic amine compound comprises

[0021] The use of the above-mentioned alkyl aromatic amine compound in the preparation of drugs containing multiple functional groups.

[0022] Furthermore, the multifunctional group-containing drug includes niclosamide, nimesulide, apixaban, D-glucose, indomethacin, pregnenolone and ezetimibe.

[0023] Beneficial effects of the present invention: The present invention overcomes the defects of traditional synthesis methods and provides a method for preparing two types of alkyl aromatic amine compounds under simple, efficient, low-cost and environmentally friendly conditions. The method completes the controllable synthesis of two types of aromatic amines under relatively neutral conditions by controlling copper salts and solvents, and the reaction has excellent chemical selectivity. The reaction can be completed under mild conditions, is compatible with almost all functional groups, and can modify various multifunctional drug molecules, including niclosamide, nimesulide, apixaban, D-glucose, indometacin, pregnenolone, and ezetimibe. BRIEF DESCRIPTION OF THE DRAWINGS

[0024] In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings required for use in the embodiments or the description of the prior art will be briefly introduced below. Obviously, for ordinary technicians in this field, other drawings can be obtained based on these drawings without paying any creative work.

[0025] Figure 1 Schematic diagram of the synthesis of the N-monoalkyl aromatic amine compound of the present invention;

[0026] Figure 2 Schematic diagram of the synthesis of N-bis-alkyl aromatic amine compounds in the present invention;

[0027] Figure 3 The structure diagrams of four types of nested carboranes in the present invention;

[0028] Figure 4 Figure 2 is a structural diagram of various multifunctional drug molecules in the present invention. DETAILED DESCRIPTION

[0029] The following will be combined with the drawings in the embodiments of the present invention to clearly and completely describe the technical solutions in the embodiments of the present invention. Obviously, the described embodiments are only 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.

[0030] Two types of alkyl aromatic amine selective synthesis implementation cases:

[0031]

[0032] This example takes the reaction of 4-bromonitrobenzene and cyclobutanone as an example to examine the effects of copper salt and solvent on the reaction selectivity and the effect of light wavelength on the reaction yield.

[0033] Take a reaction tube, add 0.2mmol 4-bromonitrobenzene as an example, 2.2 equivalents of cyclobutanone, 10mol% of copper catalyst, 0.5 equivalents of nested carborane, and 0.8mL (0.25M) of organic solvent, and react for 12h at room temperature in a nitrogen atmosphere under light. After the reaction is completed, spin dry, use petroleum ether / dichloromethane = 5 / 1-2 / 1 as eluent, and separate by silica gel column chromatography to calculate the yield.

[0034] By changing the copper salt, solvent, type of nested carborane and light wavelength range, the conditions for the N-monoalkylation and N-dialkylation of nitroaromatics and cyclobutanone were screened, and the optimal conditions for the chemical selectivity of the reaction were obtained, as shown in Table 1:

[0035] Table 1

[0036]

[0037]

[0038]

[0039]

[0040] The above results show that copper bromide (CuBr2), nested carborane nido-CB1, tert-butyl alcohol, and 395nm-400nm are the optimal reaction conditions for the synthesis of N-monoalkyl aromatic amines; tetraacetonitrile hexafluorophosphate copper [(CH3CN)4Cu + PF6 - ], nested carborane nido-CB1, tetrahydrofuran, 395nm ~ 400nm are the optimal reaction conditions

[0041]

[0042] 1 H NMR (400MHz, CDCl3): δ7.23(d,J=8.9Hz,2H),6.42(d,J=8.9Hz,2H),4.01–3.75(m,1H),3.76(br s,1H),2.53–2.32(m,2H),1.94–1.71(m,4H).

[0043] 13 C NMR (100MHz, CDCl3): δ146.30,132.05,114.64,108.99,49.06,31.21,15.38.

[0044] HRMS(ESI + )of 3b:m / z calcd for C 10 H 12 BrN[M+H] + :226.0226,Found:226.0219.

[0045]

[0046] 1 H NMR (400MHz, CDCl3): δ7.34(d,J=8.7Hz,2H), 6.74(d,J=8.7Hz,2H), 3.72–3.61(m,2H), 2.12–1.96(m,4H), 1.89–1.72(m,4H), 1.65–1.46(m,4H).

[0047] 13 C NMR (100MHz, CDCl3): δ145.95,131.28,126.55,115.47,55.17,28.81,14.90.

[0048] HRMS(ESI + ):m / z calcd for C 14 H 18 BrN[M+H] + :280.0695,Found:280.0681.

[0049] Example 1: Investigation of the adaptability of the method of the present invention to the synthesis of different N-monoalkyl aromatic amines

[0050] General method for the synthesis of N-monoalkyl aromatic amines: take a reaction tube, add 0.2 mmol nitroaromatic substrate, 1.2 equivalents of aldehyde ketone substrate, 10 mol% copper bromide catalyst, 0.5 equivalents of nested carborane nido-CB1, tert-butanol solvent or 0.8 mL (0.25 M) of a mixed solvent of ethylene glycol dimethyl ether / tert-butanol in a volume ratio of 7 / 1, react for 12 h at room temperature in a nitrogen atmosphere under light, and after the reaction is completed, spin dry, separate by silica gel column chromatography using an eluent of petroleum ether / dichloromethane in a ratio of 5 / 1-2 / 1, and calculate the yield.

[0051] Example 1-1:

[0052]

[0053] The synthesis method refers to the general method for the synthesis of N-monoalkyl aromatic amines: p-bromonitrobenzene (40 mg, 0.2 mmol), cyclododecanone (50 mg, 0.24 mmol), copper bromide (4.4 mg, 10% mol), nido-CB1 (20 mg, 0.1 mmol), PE / DCM as eluent, and a white solid with an isolated yield of 82% was obtained.

[0054] 1 H NMR (400MHz, CDCl3): δ7.22(d,J=8.4Hz,2H),6.45(d,J=8.4Hz,2H),3.55(brs,1H),3.44(tt,J=8.3,3.8Hz,1H),1.69–1.53(m,2H),1.52–1.30(m,20H).

[0055] 13 C NMR (100MHz, CDCl3): δ146.93,132.07,114.75,108.24,49.86,29.72,24.51,24.13,23.42,23.37,21.31.

[0056] HRMS(ESI + ):m / z calcd for C 18 H 28 BrN[M+H] + :338.1478,Found:338.1475.

[0057] Example 1-2:

[0058]

[0059] The synthesis method refers to the general method for the synthesis of N-monoalkyl aromatic amines: p-bromonitrobenzene (40 mg, 0.2 mmol), 2-undecanone (35 mg, 0.24 mmol), copper bromide (4.4 mg, 10% mol), nido-CB1 (20 mg, 0.1 mmol), tert-butanol 0.8 mL, PE / DCM as eluent, and a yellow liquid with an isolated yield of 80% was obtained.

[0060] 1 H NMR (400MHz, CDCl3): δ7.22(d,J=8.5Hz,2H), 6.44(d,J=8.5Hz,2H), 3.48(brs,1H), 3.43–3.35(m,1H),1.61–1.22(m,16H),1.15(d,J=6.2Hz,3H),0.88(t,J=6.6Hz,3H).

[0061] 13 C NMR (100MHz, CDCl3): δ146.80,132.76,132.05,125.14,114.74,108.25,48 .76,37.19,32.03,29.79,29.75,29.70,29.45,26.23,22.82,20.75,14.25.

[0062] HRMS(ESI + ):m / z calcd for C 17 H 28 BrN[M+H] + :326.1478,Found:326.1474.

[0063] Example 1-3:

[0064]

[0065] The synthesis method refers to the general method for the synthesis of N-monoalkyl aromatic amines: p-bromonitrobenzene (40 mg, 0.2 mmol), tetrahydrothiophene-3-one (25 mg, 0.24 mmol), copper bromide (4.4 mg, 10% mol), nido-CB1 (20 mg, 0.1 mmol), 0.8 mL of a mixed solvent of ethylene glycol dimethyl ether / tert-butyl alcohol with a volume ratio of 7 / 1, PE / DCM as the eluent, and a light yellow liquid with an isolated yield of 58% was obtained.

[0066] 1H NMR (400MHz, CDCl3): δ7.26(d,J=8.8Hz,2H),6.52(d,J=8.8Hz,2H),4.28–4.16(m,1H),3.95(br s,1H),3.12–2.74(m,4H),2.19–2.12(m,1H),2.09–2.04(m,1H)

[0067] 13 C NMR (100MHz, CDCl3): δ146.76,132.22,115.24,109.14,57.35,37.16,35.17,28.39.

[0068] HRMS(ESI + ):m / z calcd for C 10 H 12 BrNS[M+H] + :257.9947,Found:257.9944.

[0069] Example 1-4:

[0070]

[0071] The synthesis method refers to the general method for the synthesis of N-monoalkyl aromatic amines: p-bromonitrobenzene (40 mg, 0.2 mmol), adamantane ketone (36 mg, 0.24 mmol), copper bromide (4.4 mg, 10% mol), nido-CB1 (20 mg, 0.1 mmol), 0.8 mL of a mixed solvent of ethylene glycol dimethyl ether / tert-butyl alcohol with a volume ratio of 7 / 1, PE / DCM as the eluent, and an orange solid with an isolated yield of 81% was obtained.

[0072] 1 H NMR (400MHz, CDCl3): δ7.22(d,J=8.4Hz,2H),6.47(d,J=8.4Hz,2H),4.01(brs,1H),3.49(s,1H),2.01(s,2H),1.95–1.73(m,10H),1.62–1.59(m,2H).

[0073] 13 C NMR (100MHz, CDCl3): δ146.44,132.04,114.72,108.18,56.99,37.77,37.46,31.67,31.56,27.53,27.39.

[0074] HRMS(ESI + ):m / z calcd for C16 H 20 BrN[M+H] + :306.0852,Found:306.0845.

[0075] Example 1-5:

[0076]

[0077] The synthesis method refers to the general method for the synthesis of N-monoalkyl aromatic amines: p-bromonitrobenzene (40 mg, 0.2 mmol), 1-dihydroindanone (32 mg, 0.24 mmol), copper bromide (4.4 mg, 10% mol), nido-CB1 (20 mg, 0.1 mmol), 0.8 mL of a mixed solvent of ethylene glycol dimethyl ether / tert-butyl alcohol with a volume ratio of 7 / 1, PE / DCM as the eluent, and a colorless liquid with an isolated yield of 80% was obtained.

[0078] 1 H NMR (400MHz, CDCl3): δ7.34–7.30(m,1H),7.29–7.27(m,1H),7.26–7.23(m,3 H),7.23–7.16(m,1H),6.57(d,J=8.9Hz,2H),4.94(t,J=6.7Hz,1H),3.91(br s,1H),3.04–2.97(m,1H),2.92–2.84(m,1H),2.59–2.51(m,1H),1.91–1.82(m,1H)

[0079] 13 C NMR (100MHz, CDCl3): δ146.86,144.22,143.70,132.17,128.21,126.86,125.09,124.32,114.88,109.02,58.80,33.79,30.36.

[0080] HRMS(ESI + ):m / z calcd for C 15 H 14 BrN[M+H] + :288.0382,Found:288.0377.

[0081] Example 1-6:

[0082]

[0083] The synthesis method refers to the general method for the synthesis of N-monoalkyl aromatic amines: 2-nitrobenzeneboronic acid pinacol ester (50 mg, 0.2 mmol), acetone (24 mg 0.4 mmol), copper bromide (4.4 mg, 10% mol), nido-CB1 (20 mg, 0.1 mmol), 0.8 mL of a mixed solvent of ethyl acetate / tert-butanol with a volume ratio of 7 / 1, PE / DCM as the eluent, and a white solid with an isolated yield of 64% was obtained.

[0084] 1 H NMR (400MHz, CDCl3): 7.18 (dd, J = 7.7, 7.2Hz, 1H), 7.12 (d, J = 7.2Hz, 1H), 7.03 (s, 1H), 6.69 (d, J = 7.7, 1H), 3.68 (hept, J = 6.3Hz, 1H), 3.41 (br s,1H),1.33(s,12H),1.20(d,J=6.3Hz,6H).

[0085] 13 C NMR (100MHz, CDCl3): δ160.62,147.10,128.85,123.58,119.91,116.09,83.74,44.35,25.00,23.24.

[0086] HRMS(ESI + ):m / z calcd for C 15 H 24 BNO2[M+H] + :262.1973,Found:262.1968.

[0087] Example 1-7:

[0088]

[0089] The synthesis method refers to the general method for the synthesis of N-monoalkyl aromatic amines: 2,6-dichloro-4-nitropyridine (39 mg, 0.2 mmol), acetone (24 mg 0.4 mmol), copper bromide (4.4 mg, 10% mol), nido-CB1 (20 mg, 0.1 mmol), 0.8 mL of a mixed solvent of ethyl acetate / tert-butanol with a volume ratio of 7 / 1, PE / DCM as the eluent, and a yellow liquid with an isolated yield of 70% was obtained.

[0090] 1 H NMR (400MHz, CDCl3): δ6.34 (s, 2H), 4.33 (br s, 1H), 3.66–3.58 (m, 1H), 1.23 (d, J = 6.4Hz, 6H).

[0091] 13 C NMR (100MHz, CDCl3): δ155.88, 150.86, 105.89, 44.32, 22.56.

[0092] HRMS(ESI + ):m / z calcd for C8H 10 Cl2N2[M+H] + :205.0294,Found:205.0293.

[0093] Example 1-8:

[0094]

[0095] The synthesis method refers to the general method for the synthesis of N-monoalkyl aromatic amines: 4,5,6,7-tetrahydro-1-(4-methoxyphenyl)-6-(4-nitrophenyl)-7-oxo-1H-pyrazolo[3,4-C]pyridine-3-carboxylic acid ethyl ester (88 mg, 0.2 mmol), acetone (24 mg 0.4 mmol), copper bromide (4.4 mg, 10% mol), nido-CB1 (20 mg, 0.1 mmol), 0.8 mL of a mixed solvent of ethyl acetate / tert-butanol with a volume ratio of 7 / 1, PE / DCM as the eluent, and an isolated yellow solid with an isolated yield of 68% was obtained.

[0096] 1 H NMR (400MHz, DMSO-d6): δ7.46(d,J=8.7Hz,2H),7.02–6.98(m,4H),6.52(d,J=8.5Hz,2H),5.41(d,J=8.0Hz,1H),4.33(q,J=7.1Hz ,2H),3.95(t,J=6.6Hz,2H),3.80(s,3H),3.57–3.45(m,1H),3.15(t,J=6.6Hz,2H),1.32(t,J=7.1Hz,3H),1.11(d,J=6.2Hz,6H).

[0097] 13 C NMR (100MHz, DMSO-d6): δ161.43,159.24,156.37,146.61,138.33,133.33,132.52,130.17, 126.77,126.66,126.44,113.39,111.98,60.55,55.46,51.19,43.08,22.40,21.14,14.17.

[0098] HRMS(ESI + ):m / z calcd for C 25 H 28 N4O4[M+H] + :449.2183,Found:449.2168.

[0099] Example 2: Investigation of the adaptability of the method of the present invention to the synthesis of different N-dialkyl aromatic amines

[0100] General method for the synthesis of N-bis-alkyl aromatic amines: take a reaction tube, add 0.2 mmol nitroaromatic substrate, 2.4 equivalents of aldehyde ketone substrate, 10 mol% of tetraethyl cyanide copper hexafluorophosphate catalyst, 0.5 equivalents of nested carborane nido-CB1, and 0.8 mL (0.25 M) of tetrahydrofuran solvent, and react for 14 h at room temperature under nitrogen atmosphere and light. After the reaction is completed, spin dry, separate by silica gel column chromatography using an eluent of petroleum ether / dichloromethane in a ratio of 5 / 1-2 / 1, and calculate the yield.

[0101] Example 2-1:

[0102]

[0103] The synthesis method refers to the general method for the synthesis of N-bis-alkyl aromatic amines: p-methylnitrobenzene (27 mg, 0.2 mmol), cyclopropanecarboxaldehyde (34 mg, 0.48 mmol), tetraethylcyanocopper hexafluorophosphate (7.2 mg, 10% mol), nido-CB1 (20 mg, 0.1 mmol), tetrahydrofuran solvent 0.8 mL, PE / DCM as eluent, and a colorless liquid with an isolated yield of 94% was obtained.

[0104] 1 H NMR (400MHz, CDCl3): δ7.05(d,J=8.6Hz,2H),6.78(d,J=8.6Hz,2H),3.25(d,J=6 .1Hz,4H),2.27(s,3H),1.16–0.95(m,2H),0.58–0.44(m,4H),0.35–0.12(m,4H).

[0105] 13 C NMR (100MHz, CDCl3): δ147.27,129.73,125.44,113.50,55.49,20.34,9.56,3.97.

[0106] HRMS(ESI + ):m / z calcd for C 15 H 21 N[M+H]+ :216.1747,Found:216.1742

[0107] Example 2-2:

[0108]

[0109] The synthesis method refers to the general method for the synthesis of N-bis-alkyl aromatic amines: p-methylnitrobenzene (27 mg, 0.2 mmol), cyclobutanone (34 mg 0.48 mmol), tetraethylcyanocopper hexafluorophosphate (7.2 mg, 10% mol), nido-CB1 (20 mg, 0.1 mmol), tetrahydrofuran solvent 0.8 mL, PE / DCM as eluent, and a colorless liquid with an isolated yield of 77% was obtained.

[0110] 1 H NMR (400MHz, CDCl3): δ7.07 (d, J = 8.0 Hz, 2H), 6.84 (d, J = 8.0 Hz, 2H), 3.63 (tt, J = 9. 2,7.0Hz,2H),2.31(s,3H),2.07–1.95(m,4H),1.91–1.73(m,4H),1.60–1.52(m,4H)

[0111] 13 C NMR (100MHz, CDCl3): δ144.16,132.78,128.98,125.74,55.69,28.79,20.96,15.01.

[0112] HRMS(ESI + ):m / z calcd for C 15 H 21 N[M+H] + :216.1747,Found:216.1743.

[0113] Example 2-3:

[0114]

[0115] The synthesis method refers to the general method for the synthesis of N-bis-alkyl aromatic amines: 5-nitrobenzofuran-2-carboxylic acid ethyl ester (47 mg, 0.2 mmol), cyclobutylcarboxaldehyde (40 mg, 0.48 mmol), tetraethylcyanocopper hexafluorophosphate (7.2 mg, 10% mol), nido-CB1 (20 mg, 0.1 mmol), tetrahydrofuran solvent 0.8 mL, PE / DCM as eluent, and a green liquid with an isolated yield of 60% was obtained.

[0116] 1H NMR (400MHz, CDCl3): δ7.45–7.35(m,2H),6.94(dd,J=9.3,2.6Hz,1H),6.82(d,J=2.6Hz,1H),4.42(q,J=7.1Hz,2H),3. 28(d,J=6.9Hz,4H),2.67–2.57(m,2H),2.12–1.95(m,4H),1.91–1.78(m,4H),1.77–1.64(m,4H),1.42(t,J=7.1Hz,3H).

[0117] 13 C NMR (100MHz, CDCl3): δ159.93,149.64,146.76,145.79,127.81,117.63,113.96,112.36,105.55,61.43,58.53,34.33,27.33,18.80,14.50.

[0118] HRMS(ESI + ):m / z calcd for C 21 H 27 NO3[M+H] + :342.2064,Found:342.2050.

[0119] Example 2-4:

[0120]

[0121] The synthesis method refers to the general method for the synthesis of N-bis-alkyl aromatic amines: niclosamide (65 mg, 0.2 mmol), cyclobutylcarboxaldehyde (40 mg, 0.48 mmol), tetraethylcyanocopper hexafluorophosphate (7.2 mg, 10% mol), nido-CB1 (20 mg, 0.1 mmol), tetrahydrofuran solvent 0.8 mL, PE / DCM as eluent, and a yellow liquid with an isolated yield of 72% was obtained.

[0122] 1H NMR (400MHz, CDCl3): δ12.00 (br s,1H),8.10(s,1H),7.87(d,J=9.2Hz,1H),7.50(d,J=2.4Hz,1H),7.37(dd,J=8.9,2.4Hz,1H),6.97(d,J=8.9Hz,1H),6.65(d,J=2.9Hz ,1H),6.58(dd,J=9.2,2.9Hz,1H),3.30(d,J=6.9Hz,4H),2.77–2.51(m,2H),2.08–2.01(m,4H),1.93–1.80(m,4H),1.79–1.65(m,4H).

[0123] 13 C NMR (100MHz, CDCl3): δ166.85,160.39,147.51,134.44,126.74,125.19,124.65 ,123.76,121.23,120.44,115.86,112.43,111.57,57.05,34.29,27.26,18.77.

[0124] HRMS(ESI + ):m / z calcd for C 23 H 26 Cl2N2O2[M+H] + :433.1444,Found:433.1430.

[0125] Example 2-5:

[0126]

[0127] The synthesis method refers to the general method for the synthesis of N-bis-alkyl aromatic amines: nimesulide (61 mg, 0.2 mmol), cyclobutylcarboxaldehyde (40 mg, 0.48 mmol), tetraethylcyanocopper hexafluorophosphate (7.2 mg, 10% mol), nido-CB1 (20 mg, 0.1 mmol), tetrahydrofuran solvent 0.8 mL, PE / DCM as eluent, and a yellow liquid with an isolated yield of 82% was obtained.

[0128] 1H NMR (400MHz, CDCl3): δ7.38–7,34(m,3H),7.13(t,J=7.4Hz,1H),6.99(d,J=8.0Hz,2H),6.38(dd,J=9.0,2.8Hz,1H),6.17(s,1H),6. 10(d,J=2.8Hz,1H),3.20(d,J=6.7Hz,4H),2.91(s,3H),2.57–2.50(m,2H),1.97–1.94(m,4H),1.89–1.72(m,4H),1.71–1.54(m,4H).

[0129] 13 C NMR (100MHz, CDCl3): δ156.45,150.56,148.88,130.15,127.80,123.92,118.29,115.01,108.35,102.67,57.09,39.12,34.37,27.24,18.71.

[0130] HRMS(ESI + )of:m / z calcd for C 23 H 30 N2O3S[M+H] + :415.2050,Found:415.2039.

[0131] In the description of this specification, the description with reference to the terms "one embodiment", "example", "specific example", etc. means that the specific features, structures, materials or characteristics described in conjunction with the embodiment or example are included in at least one embodiment or example of the present invention. In this specification, the schematic representation of the above terms does not necessarily refer to the same embodiment or example. Moreover, the specific features, structures, materials or characteristics described can be combined in any one or more embodiments or examples in a suitable manner.

[0132] The above shows and describes the basic principles, main features and advantages of the present invention. Those skilled in the art should understand that the present invention is not limited to the above embodiments, and the above embodiments and descriptions are only for explaining the principles of the present invention. Without departing from the spirit and scope of the present invention, the present invention may have various changes and improvements, and these changes and improvements all fall within the scope of the present invention to be protected.

Claims

1. A selective and controllable synthesis method of two types of alkyl aromatic amine compounds, characterized in that: The synthesis method comprises the following steps: S1, mixing nitroaromatic hydrocarbon with aromatic aldehyde / ketone or alkyl aldehyde / ketone, and then adding copper salt, nested carborane and organic solvent to obtain a mixture; S2, irradiating the mixture with blue light at 25°C-80°C under inert gas protection to obtain a product; S3. After the reaction is completed, the product is separated and purified to obtain an N-monoalkyl aromatic amine compound or an N-dialkyl aromatic amine compound; The molar ratio of the nitroaromatic hydrocarbon, aromatic aldehyde / ketone or alkyl aldehyde / ketone, copper salt and nested carborane is 10:(12-24):1:5; the molar concentration of the nitroaromatic hydrocarbon in the organic solvent is 0.25M; The reaction formula is: Ar is one of benzene, naphthalene, phenanthrene, pyrazine, pyridazine, benzofuran, benzothiazole, 1,2-benzopyrone, indole, quinoline, and isoquinoline; The R 1 ~R 5 One or more selected from H, F, Cl, Br, I, NH2, -CN, -CHO, -Bpin, C1-C10 alkyl, C2-C10 alkenyl, C3-C10 alkynyl, C1-C10 alkoxy, phenylethynyl, cyclopropane, halogenated alkyl, cyclohexenyl, benzaldehyde, tetraphenylethylene, ethyl acetate, isobutylamide; R 6 , R 7 One or two selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, trihalomethyl, etc.

2. The selective and controllable synthesis method of two types of alkyl aromatic amine compounds according to claim 1, characterized in that: The aryl group is phenyl, thiophene, furan, pyrrole, pyrazole or pyridine substituted by one or more of H, F, Cl, Br, I, -CHO, C1-C10 alkoxy, C3-C10 alkoxycarbonyl, C2-C10 alkenyl, and phenyl.

3. The selective and controllable synthesis method of two types of alkyl aromatic amine compounds according to claim 1, characterized in that: The copper salt reagent is selected from one of cuprous iodide, cuprous bromide, cuprous chloride, cuprous chloride, cuprous thiocyanate, tetraacetonitrile copper hexafluorophosphate, cupric bromide, cupric chloride, cupric acetate, and copper trifluorosulfonate.

4. The selective and controllable synthesis method of two types of alkyl aromatic amine compounds according to claim 1, characterized in that: The nested carborane is one of nido-CB1, nido-CB2, nido-CB3 or nido-CB4.

5. The selective and controllable synthesis method of two types of alkyl aromatic amine compounds according to claim 1, characterized in that: The organic solvent is selected from one or more of dichloromethane, dichloroethane, acetonitrile, methanol, ethanol, tetrahydrofuran, tert-butanol, ethylene glycol dimethyl ether, ethyl acetate, and 1,4-dioxane.

6. The selective and controllable synthesis method of two types of alkyl aromatic amine compounds according to claim 1, characterized in that: The wavelength of the blue light is 395nm-400nm; the irradiation time is 3-14 hours.

7. An alkyl aromatic amine compound comprising 8. Use of the alkyl aromatic amine compound as claimed in claim 7 in the preparation of a drug containing multiple functional groups.

9. The use according to claim 9, characterized in that: The multifunctional group-containing drugs include niclosamide, nimesulide, apixaban, D-glucose, indomethacin, pregnenolone and ezetimibe.

Images