A metal-free synthesis method for aromatic amine compounds

Abstract

The present invention discloses a metal-free synthesis method for aromatic amine compounds. Cyclohexenone or tetrahydro-2-naphthone compounds and various amines are used as raw materials. In the presence of a catalyst, a wide range of substrates can be selected. Compared with traditional synthesis methods, the method has the advantages of simple conditions and convenient operation because no metal catalyst is used. The yield is also relatively high (up to 90%), the pollution to the environment is small, and the method is easy to industrialize.

Description

Technical Field

[0001] The invention belongs to the technical field of organic synthesis, and particularly relates to a method for synthesizing aromatic amine compounds without metal participation. Background Art

[0002] Aromatic amines are an important class of organic synthesis intermediates. Their basic structural units are widely found in the molecular structures of a large number of natural products, pharmaceuticals, and materials, and are therefore commonly used in the fields of biology, medicine, and materials. Some progress has been made in the synthesis of these compounds.

[0003] A common industrial method for synthesizing aromatic amines is through the reduction of the nitro group. Aromatic amine compounds can be obtained by metal reduction in acidic, alkaline, or neutral systems, such as zinc powder reduction and hydrazine hydrate reduction. While these traditional preparation processes offer wide applicability, ease of operation, and high product quality, they also pose significant environmental risks. Catalytic hydrogenation is expensive and places stringent demands on catalyst activity and hydrogenation conditions. Therefore, the development of efficient, clean, and affordable methods for synthesizing aromatic amines is imperative. Subsequently, metal-catalyzed coupling reactions for synthesizing aromatic amines were developed, including the copper-catalyzed Ullmann reaction and the palladium-catalyzed Buchwald reaction. However, the halogenated aromatics used in this type of reaction have low activity. Considering the economic efficiency of copper catalysis, the Ullmann-Ma reaction under mild conditions was developed [(a) Thomas. et al. Angew. Chem. Int. Ed. 2003, 42, 5400. (b) Li C. et al. Chem. Sci., 2015, 6, 4174. (c) Ma D. et al. J. Am. Chem. Soc. 2015, 137, 37, 11942.].

[0004] The above methods all prepare aromatic amines from aromatic compounds. However, with the development of green and sustainable chemistry, the direct preparation of aromatic compounds, particularly aromatic amines, from unsaturated compounds has become a new strategy. Recently, methods for the synthesis of aromatic amines through the coupling aromatization of cyclohexenone with amines have emerged, primarily relying on transition metal Pd catalysts. For example, Pd / C-catalyzed oxidative amination of cyclohexenone with ethylene as a hydrogen acceptor has been developed to avoid the use of metal catalysts. Systems for the coupling of cyclohexenone with aromatic amines in the presence of catalytic p-toluenesulfonic acid and the synthesis of diarylamines using elemental iodine / dimethyl sulfoxide systems have been developed. [(a) M. Hayashi. et al. Adv. Synth. Catal. 2018, 360, 3297–3305. (b) CD Maycock. et al. Chem. Commun. 2012, 48, 10901. (c) Pan Y. et al. Chem. Commun. 2018, 54, 9679.] However, elemental iodine is very harmful to the human body. At the same time, the above catalytic system has great limitations on the scope of application of amines and easily generates iodine-containing by-products. Therefore, there is an urgent need to develop a synthesis method with a wider range of applications, greater efficiency and greenness. Summary of the Invention

[0005] In order to overcome the above-mentioned shortcomings of the prior art, the purpose of the present invention is to provide a metal-free synthesis method for aromatic amine compounds to solve the technical problems of the prior art such as limited substrate range, metal residues and complicated operations.

[0006] In order to achieve the above object, the present invention adopts the following technical solutions:

[0007] The present invention discloses a method for synthesizing an aromatic amine compound without metal participation, wherein a ketone-containing compound and an amine-containing compound are mixed and reacted in the presence of a non-metallic catalyst and an additive to obtain the aromatic amine compound.

[0008] in:

[0009] The amine-containing compound is an alkylamine or an aromatic amine;

[0010] The structural formula of the ketone-containing compound is as follows:

[0011]

[0012] The structural formula of the prepared aromatic amine compound is as follows:

[0013]

[0014] wherein R is selected from hydrogen, alkyl, alkoxy, substituted aryl, ester or halogen substituents; R 1 and R 2Selected from aliphatic amines, aromatic amines, amino acid esters or amino alcohols.

[0015] Preferably, the non-metallic catalyst is methyltriphenylphosphine iodide, tetraethylammonium iodide, tetrapropylammonium iodide, benzyltrimethylammonium iodide, tetraheptylammonium iodide, tetrabutylammonium iodide, magnesium iodide or sodium iodide.

[0016] Preferably, the added additive is selected from N,N-diisopropylethylamine, 2,6-lutidine, N,N-dimethylaniline, sodium bicarbonate or ammonium acetate.

[0017] Preferably, the reaction temperature is 60-110°C.

[0018] More preferably, the reaction temperature is 100°C.

[0019] Preferably, the molar ratio of the ketone-containing compound to the non-metallic catalyst is 4:1 to 2:1.

[0020] Preferably, the reaction molar ratio of the ketone-containing compound to the amine-containing compound is 3:1 to 1:3.

[0021] Preferably, the reaction added solvent is selected from 1,2-dichloroethane, 1,2-dibromoethane, dichloromethane, chloroform, carbon tetrachloride, ethyl acetate, methyl acetate, butyl acetate, acetone, nitromethane, acetonitrile, toluene, benzene, chlorobenzene, n-hexane, tetrahydrofuran, 1,4-dioxane, diethyl ether, N,N-dimethylformamide, N,N-dimethylacetamide, methanol or ethanol, etc.

[0022] Preferably, the concentration of the solvent is 0.5 to 2 mol / L.

[0023] Compared with the prior art, the present invention has the following beneficial effects:

[0024] The metal-free synthesis method of aromatic amine compounds disclosed in the present invention uses cyclohexenone or tetrahydro-2-naphthone compounds and various amines as raw materials, and reacts to generate substituted aromatic amines under the action of a catalyst. A wide range of substrates can be selected. Compared with traditional synthesis methods, since no metal catalyst is used, the method has the advantages of simple conditions and convenient operation, and a relatively high yield (up to 90%), low environmental pollution, and easy industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0025] Figure 1 The figure is a reaction synthesis route diagram of the present invention. DETAILED DESCRIPTION

[0026] In order to enable those skilled in the art to better understand the solutions of the present invention, the technical solutions in the embodiments of the present invention will be clearly and completely described below in conjunction with the drawings in the embodiments of the present invention. Obviously, the embodiments described 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 making creative efforts should fall within the scope of protection of the present invention.

[0027] It should be noted that the terms "first", "second", etc. in the description and claims of the present invention and the above-mentioned drawings are used to distinguish similar objects and are not necessarily used to describe a specific order or sequence. It should be understood that the numbers used in this way can be interchanged where appropriate, so that the embodiments of the present invention described herein can be implemented in an order other than those illustrated or described herein. In addition, the terms "including" and "having" and any variations thereof are intended to cover non-exclusive inclusions. For example, a process, method, system, product or device that includes a series of steps or units is not necessarily limited to those steps or units clearly listed, but may include other steps or units that are not clearly listed or inherent to these processes, methods, products or devices.

[0028] The present invention is described in further detail below with reference to the accompanying drawings:

[0029] See also Figure 1 , which is a roadmap for the metal-free synthesis of aromatic amine compounds disclosed in the present invention. The present invention is to mix a cyclohexenone or tetrahydro-2-naphthone compound having the general formula I with an amine compound having the general formula II, including an alkylamine or an aromatic amine, and react them in the presence of a catalyst to obtain the substituted aromatic amine compound of the general formula III.

[0030] Wherein R is selected from hydrogen, alkyl, alkoxy, substituted aryl, ester, and halogen substituents.

[0031] where R 1 ,R 2 Selected from aliphatic amines, aromatic amines, amino acid esters, and amino alcohols.

[0032] Wherein, the catalyst is selected from any one of methyltriphenylphosphine iodide, tetraethylammonium iodide, tetrapropylammonium iodide, benzyltrimethylammonium iodide, tetraheptylammonium iodide, tetrabutylammonium iodide, magnesium iodide, and sodium iodide.

[0033] The added additive is selected from any one of N,N-diisopropylethylamine, 2,6-lutidine, N,N-dimethylaniline, sodium bicarbonate and ammonium acetate.

[0034] Wherein, the molar ratio of the cyclohexenone or tetrahydro-2-naphthone compound of general formula I to the catalyst is 4:1 to 2:1.

[0035] Wherein, the reaction temperature is 60-110°C.

[0036] Preferably, the reaction temperature is 100°C.

[0037] The solvent is selected from any one of 1,2-dichloroethane, 1,2-dibromoethane, dichloromethane, chloroform, carbon tetrachloride, ethyl acetate, methyl acetate, butyl acetate, acetone, nitromethane, acetonitrile, toluene, benzene, chlorobenzene, n-hexane, tetrahydrofuran, 1,4-dioxane, ether, N,N-dimethylformamide, N,N-dimethylacetamide, methanol, and ethanol, and the concentration is 0.5 to 2 mol / L.

[0038] Example 1 Synthesis of N-benzyl-3-methylaniline

[0039]

[0040] Take a 25mL reaction tube, add 14.8mg of tetrabutylammonium iodide, 22.0mg of 3-methylcyclohex-2-en-1-one, and 42.9mg of benzylamine, MS 150 mg, N,N-dimethylaniline 48.5 mg, 1,2-dichloroethane 1 mL, stirred at 100°C for 24 hours. After the reaction, ethyl acetate 10 mL was added and washed with brine 5 mL. The organic phase was separated, and the aqueous phase was extracted three times with ethyl acetate. The combined organic phases were separated by column chromatography using a developing solvent of petroleum ether:ethyl acetate in a ratio of 40:1 to 10:1 to obtain 16.6 mg of pure N-benzyl-3-methylaniline in a 42% yield.

[0041] 1 H NMR (CDCl3, 400MHz): δ7.37–7.30 (m, 4H), 7.30–7.23 (m, 1H), 7.05 (t, J = 8.0Hz, 1H), 6.53(d,J=8.0Hz,1H),6.48–6.40(m,2H),4.29(s,2H),3.91(brs,1H),2.25(s,3H). 13 CNMR(CDCl3,101MHz): δ148.35,139.69,139.13,129.26,128.72,127.64,127.30,118.64,113.75,110.08,48.45,21.74ppm.

[0042] Example 2 Synthesis of N-benzyl-3-phenylaniline

[0043]

[0044] Take a 25mL reaction tube, add 14.8mg of tetrabutylammonium iodide, 34.4mg of 3-phenylcyclohex-2-en-1-one, and 42.9mg of benzylamine, MS 150 mg, N,N-dimethylaniline 48.5 mg, 1,2-dichloroethane 1 mL, stirred at 100°C for 24 hours. After the reaction, ethyl acetate 10 mL was added and washed with brine 5 mL. The organic phase was separated, and the aqueous phase was extracted three times with ethyl acetate. The combined organic phases were separated and purified by column chromatography using a developing solvent of petroleum ether:ethyl acetate in a ratio of 40:1 to 10:1 to obtain 28.5 mg of pure N-benzyl-3-phenylaniline in a 55% yield.

[0045] 1 H NMR (CDCl3, 400MHz): δ7.59 (d, 2H, J = 7.6), 7.23–7.48 (m, 9H,), 6.99 (d, 1H, J = 7. 8Hz), 6.89 (t, 1H, J = 2.0Hz), 6.66 (d, 1H, J = 8.0Hz), 4.42 (s, 2H), 4.15 (brs, 1H). 13 C NMR (CDCl3, 101MHz): δ148.5,142.4,141.7,139.4,129.7,128.7,128.6,127.6,127.3,127.2(2C),116.8,111.9,111.7,48.4ppm.

[0046] Example 3 Synthesis of N-benzyl-2-naphthylamine

[0047]

[0048] Take a 25mL reaction tube, add 14.8mg of catalyst tetrabutylammonium iodide, 29.2mg of tetrahydro-2-naphthalenone, and 42.9mg of benzylamine, MS 150 mg, N,N-dimethylaniline 48.5 mg, 1,2-dichloroethane 1 mL, stirred at 100°C for 16 hours. After the reaction, ethyl acetate 10 mL was added and washed with brine 5 mL. The organic phase was separated, and the aqueous phase was extracted three times with ethyl acetate. The combined organic phases were separated by column chromatography using a developing solvent of petroleum ether:ethyl acetate in a ratio of 40:1 to 10:1 to obtain 41.5 mg of pure N-benzyl-2-naphthylamine in an 89% yield.

[0049] 1H NMR (400MHz, CDCl3): δ7.69-7.58(m,3H),7.44-7.28(m,6H),7.22-7.18(m,1H),6.94-6.91(m,1H),6.85(d,1H,J=2.0Hz),4.45(s,2H),4.21(brs,1H)

[0050] Example 4 Synthesis of N-substituted benzyl-2-naphthylamine

[0051]

[0052] R 3 = any one of 4-F, 4-Me, 4-OMe, and 4-Br;

[0053] Take a 25mL reaction tube, add 14.8mg of tetrabutylammonium iodide, 0.2mmol of tetrahydro-2-naphthalenone, and 0.4mmol of substituted benzylamine, MS 150 mg, N,N-dimethylaniline 48.5 mg, 1,2-dichloroethane 1 mL, stirred at 100°C for 14 hours. After the reaction, ethyl acetate 10 mL was added and washed with brine 5 mL. The organic phase was separated and the aqueous phase was extracted three times with ethyl acetate. The combined organic phases were separated and purified by column chromatography using a developing solvent of petroleum ether:ethyl acetate in a ratio of 40:1 to 10:1 to obtain the pure substituted 2-naphthylamine.

[0054] according to Figure 1 The reaction synthesis route shown corresponds to the corresponding raw materials I and II, and the experimental results are listed in Table 1:

[0055] Table 1 Non-metal-catalyzed aromatization of tetrahydro-2-naphthalenone with substituted benzylamines

[0056]

[0057] Compound a: N-(4-fluorobenzyl)-2-naphthylamine

[0058] 1H NMR (500MHz, CDCl3) δ7.70 (dd, J=17.1, 8.4Hz, 2H), 7.62 (d, J=8.2Hz, 1H), 7.44–7.37 (m, 3H), 7.2 7–7.22(m,1H),7.07(t,J=8.7Hz,2H),6.96(dd,J=8.8,2.3Hz,1H),6.87(s,1H),4.44(s,2H).13C NMR (126MHz, CDCl3) δ162.2 (d, J = 245.1Hz), 145.1, 135.0, 134.5, 129.3 (d, J = 8.0Hz) ,129.1,127.8,127.7,126.3(d,J=46.0Hz),122.4,118.0,115.6,115.5,105.3,47.9. 19 F NMR (471MHz, CDCl3) δ-115.30ppm.

[0059] Compound b: N-(4-methylbenzyl)-2-naphthylamine

[0060] 1 H NMR (500MHz, CDCl3) δ7.72(d,J=8.0Hz,1H),7.66(dd,J=16.2,8.5Hz,2H),7.40(t,J=7.5Hz,1H),7.35( d,J=7.6Hz,2H),7.27–7.18(m,3H),6.96(dd,J=8.7,2.3Hz,1H),6.91(s,1H),4.43(s,2H),2.40(s,3H). 13 C NMR (126MHz, CDCl3) δ145.6,137.1,135.9,135.2,129.4,129.0,127.8,127.7,126.4,126.1,122.2,118.0,105.0,48.3,21.2ppm.

[0061] Compound c: N-(4-methoxybenzyl)-2-naphthylamine

[0062] 1 H NMR (500MHz, CDCl3) δ7.71 (d, J=8.1Hz, 1H), 7.66 (dd, J=14.4, 8.5Hz, 2H), 7.39 (dd, J= 15.7,7.8Hz,3H),7.24(t,J=3.9Hz,1H),6.98–6.89(m,4H),4.39(s,2H),3.84(s,3H). 13C NMR (126MHz, CDCl3) δ159.0,145.5,135.1,130.9,129.1,129.0,127.7,126.4,126.1,122.2,118.1,114.1,105.1,55.4,48.1ppm.

[0063] Compound d: N-(1-phenylethyl)-2-naphthylamine

[0064] 1 H NMR (400MHz, CDCl3): δ=7.99-7.96(m,1H),7.84-7.82(m,1H),7.53-7.46(m,4H),7.37(t,J=8.0Hz,2H),7.30-7.26(m,1H),7.2 3(t,J=2.4Hz,2H),6.42(dd,J1=3.6Hz,J2=5.2Hz,1H),4.78(s,1H),4.73(q,J1=6.8Hz,J2=13.2Hz,1H),1.71(d,J=6.8Hz,3H); 13 C NMR (100MHz, CDCl3): δ=144.94,142.11,134.28,128.78,128.71,126.98,126. 57,125.83,125.64,124.70,123.25,119.77,117.23,106.02,53.58,25.27ppm.

[0065] Compound e: N-methyl-N-benzyl-2-naphthylamine

[0066] 1 H NMR(500MHz, CDCl3)δ7.72(d,J=8.8Hz,2H),7.67(d,J=8.2Hz,1H),7.41–7.34(m,3H), 7.33–7.28(m,3H),7.27–7.18(m,2H),7.00(d,J=2.1Hz,1H),4.69(s,2H),3.14(s,3H). 13 C NMR (126MHz, CDCl3) δ147.7,138.8,135.1,128.9,128.6,127.5,127.0,126.9,126.9,126.3,126.2,122.1,116.2,106.2,56.8,38.7ppm.

[0067] Example 5 Synthesis of N-substituted phenethyl-2-naphthylamine

[0068]

[0069] R 4 =H, 4-F, or 2-Br.

[0070] Take a 25mL reaction tube, add 14.8mg of tetrabutylammonium iodide, 0.2mmol of tetrahydro-2-naphthalenone, and 0.4mmol of substituted phenylethylamine, MS 150mg, N,N-dimethylaniline 48.5mg, 1,2-dichloroethane 1mL, stirred at 100℃ for 14 hours. After the reaction, 10mL of ethyl acetate was added and washed with 5mL of brine. The organic phase was separated and the aqueous phase was extracted 3 times with ethyl acetate. The organic phases were combined and separated by column chromatography with a developing solvent of petroleum ether: ethyl acetate in a ratio of 40:1 to 10:1 to obtain the pure substituted 2-naphthylamine. Figure 1 The reaction synthesis route shown corresponds to the corresponding raw materials I and II, and the experimental results are listed in Table 2:

[0071] Table 2 Non-metal-catalyzed aromatization of tetrahydro-2-naphthalenone with substituted phenylethylamines

[0072]

[0073] Compound f: N-phenylethyl-2-naphthylamine

[0074] 1 H NMR(500MHz, CDCl3)δ7.74(d,J=8.1Hz,1H),7.69(dd,J=8.4,3.7Hz,2H),7.47–7.38(m, 3H),7.35–7.27(m,4H),6.95–6.89(m,2H),3.57(t,J=7.0Hz,2H),3.05(t,J=7.0Hz,2H). 13 C NMR (126MHz, CDCl3) δ145.5,139.3,135.3,129.1,128.9,128.7,127.7,127.7,126.6,126.4,126.0,122.1,118.2,104.9,45.2,35.3ppm.

[0075] Compound g: N-(4-fluorophenethyl)-2-naphthylamine

[0076] 1H NMR (500MHz, CDCl3) δ7.72(d,J=8.1Hz,1H),7.67(d,J=8.9Hz,2H),7.41(dd,J=7.9,7.1Hz,1H),7.27–7 .20(m,3H),7.06(t,J=8.6Hz,2H),6.88(d,J=6.7Hz,2H),3.52(t,J=7.0Hz,2H),2.99(t,J=6.9Hz,2H). 13 C NMR (126MHz, CDCl3) δ161.7 (d, J = 244.3Hz), 145.5, 135.2, 134.9 (d, J = 3.0Hz), 130.3 (d, J = 7.6 Hz), 129.1, 127.7, 127.6, 126.4, 126.0, 122.1, 118.1, 115.5 (d, J = 21.1Hz), 104.7, 45.1, 34.4. 19 F NMR (471MHz, CDCl3) δ-116.62ppm.

[0077] Example 6 Synthesis of N-substituted phenyl-2-naphthylamine

[0078]

[0079] R 5 =H, 4-NO2, 4- t Any of Bu, 4-CF3

[0080] Take a 25mL reaction tube, add 14.8mg of catalyst tetrabutylammonium iodide, 0.2mmol of corresponding tetrahydro-2-naphthalenone raw material, 0.4mmol of N-substituted aniline, MS 150mg, N,N-dimethylaniline 48.5mg, 1,2-dichloroethane 1mL, stirred at 100℃ for 14 hours. After the reaction, 10mL of ethyl acetate was added and washed with 5mL of brine. The organic phase was separated and the aqueous phase was extracted 3 times with ethyl acetate. The organic phases were combined and separated by column chromatography with a developing solvent of petroleum ether: ethyl acetate in a ratio of 40:1 to 10:1 to obtain the pure substituted 2-naphthylamine. Figure 1 The reaction synthesis route shown corresponds to the corresponding raw materials I and II, and the experimental results are listed in Table 3:

[0081] Table 3 Non-metal-catalyzed aromatization of tetrahydro-2-naphthalenone with substituted anilines

[0082]

[0083] Compound h: N-(4-tert-butylphenyl)-2-naphthylamine

[0084] 1 H NMR (400MHz, CDCl3) δ7.74(d,J=8.9Hz,2H),7.65(d,J=8.3Hz,1H),7.43–7.33(m,4H),7.29(t ,J=7.5Hz,1H),7.21(dd,J=8.8,2.3Hz,1H),7.14(d,J=8.5Hz,2H),5.84(bs,1H),1.35(s,9H); 13 C NMR (101MHz, CDCl3) δ144.74,141.51,140.21,134.82,129.24,129.05,127.76,126.52,126.35,123.35,119.86,118.64,110.73,34.39,31.63ppm.

[0085] Compound i: N-phenyl-2-naphthylamine

[0086] 1 H NMR(500MHz, CDCl3)δ7.85–7.80(m),7.73(d,J=8.2Hz),7.55–7.48(m),7.44 –7.36(m),7.30–7.27(m),7.24(dd,J=8.5,1.0Hz),7.08(dd,J=10.6,4.1Hz). 13 C NMR (126MHz, CDCl3) δ143.0,140.9,134.7,129.6,129.3,129.3,127.8,126.6,126.6,123.6,121.5,120.1,118.3,111.6ppm.

[0087] Compound j: N-(4-nitrophenyl)-2-naphthylamine

[0088] 1 H NMR (400MHz, CDCl3) δ8.19-8.12(m,2H),7.85(dd,J=14.5,8.4Hz,2H),7.76(d,J=8.1Hz,1H),7.64(d,J=2.2Hz, 1H), 7.47 (dddd, J=22.2, 8.2, 6.9, 1.3Hz, 2H), 7.33 (dd, J=8.7, 2.3Hz, 1H), 7.07-7.00 (m, 2H), 6.46 (s, 1H)ppm.

[0089] Example 7 Synthesis of N-substituted alkyl-2-naphthylamine

[0090]

[0091] R 6 = any one of n-butyl, cyclopropyl, cyclohexyl, morpholine, isopropyl, tetrahydropyrrole

[0092] Take a 25mL reaction tube, add 14.8mg of catalyst tetrabutylammonium iodide, 0.2mmol of tetrahydro-2-naphthalenone raw material, and 0.4mmol of N-substituted aniline, MS 150mg, N,N-dimethylaniline 48.5mg, 1,2-dichloroethane 1mL, stirred at 100℃ for 14 hours. After the reaction, 10mL of ethyl acetate was added and washed with 5mL of brine. The organic phase was separated and the aqueous phase was extracted 3 times with ethyl acetate. The organic phases were combined and separated by column chromatography with a developing solvent of petroleum ether: ethyl acetate in a ratio of 40:1 to 10:1 to obtain the pure substituted 2-naphthylamine. Figure 1 The reaction synthesis route shown in the figure takes the corresponding raw materials I and II, and the experimental results are listed in Table 4:

[0093] Table 4 Non-metal-catalyzed aromatization of tetrahydro-2-naphthalenone with alkylamines

[0094]

[0095]

[0096] Compound k: N-isopropyl-2-naphthylamine

[0097] 1 H NMR (600MHz, CDCl3): δ = 7.84 (m, 1H), 7.57 (d, J = 8.4Hz, 1H), 7.52 (m, 2H), 7.26 (t, J = 8.4Hz, 1H),7.09(t,J=8.4Hz,1H),6.73(s,1H),3.67(m,1H),3.64(brs,1H),1.19(d,J=6.0Hz,6H). 13 C NMR (151MHz, CDCl3,): δ=145.6,145.0,135.9,135.3,132.0,130.1,129.8,129.6,129.0,12 8.1,128.0,127.7,127.4,126.3,125.9,124.7,121.9,119.4,118.4,105.2,44.5,22.9ppm.

[0098] Compound 1: N-(2-naphthyl)tetrahydropyrrole

[0099] 1H NMR (500MHz, CDCl3) δ7.78(dd,J=8.6,4.4Hz),7.73(d,J=8.2Hz),7.45(ddd,J=8.3,6.7,1.3Hz),7.26(ddd,J =8.1,6.7,1.2Hz),7.08(dd,J=9.0,2.5Hz),6.85(d,J=2.5Hz),3.51–3.45(m),2.12(dq,J=6.7,3.8,3.2Hz). 13 C NMR (126MHz, CDCl3)145.9,135.3,128.9,127.7,126.4,126.2,125.9,121.3,115.8,104.8,47.9,25.6ppm.

[0100] Compound m: 4-(2-naphthyl)morpholine

[0101] 1 H NMR (500MHz, CDCl3) δ7.82–7.72(m,3H),7.46(t,J=7.5Hz,1H),7.36(t,J=7.5Hz,1H),7.29 (dd,J=9.0,2.5Hz,1H),7.16(d,J=2.2Hz,1H),3.95(t,J=1.1Hz,4H),3.29(t,J=1.1Hz,4H). 13 C NMR (126MHz, CDCl3) δ149.1,134.6,128.9,128.7,127.5,126.9,126.4,123.6,119.0,110.2,67.0,49.9ppm.

[0102] Compound n: N-cyclopropyl-2-naphthylamine

[0103] 1 H NMR (400MHz, CDCl3): δ7.78-7.66(m,3H),7.48-7.40(m,2H),7.30-7.25(m,1H),7.18(m,1H) ,6.97–6.92(m,2H),4.32(brs,1H),2.60–2.53(m,1H),0.87–0.81(m,2H),0.64–0.59(m,2H). 13 C NMR (100MHz, CDCl3): δ146.42,135.20,128.86,127.81,127.75,126.34,126.14,122.10,117.76,105.61,25.39,7.55ppm.

[0104] Example 8 Synthesis of N-benzyl-substituted-2-naphthylamine

[0105]

[0106] R 7 = any one of 7-methoxy, 6-bromo, 6-fluoro, 5-methoxy, 1-methyl, 1-phenyl, 1-(2-methoxy)naphthyl

[0107] Take a 25mL reaction tube, add 14.8mg of catalyst tetrabutylammonium iodide, 0.2mmol of corresponding tetrahydro-2-naphthalenone raw material, and 0.4mmol of benzylamine, MS 150mg, N,N-dimethylaniline 48.5mg, 1,2-dichloroethane 1mL, stirred at 100℃ for 14 hours. After the reaction, 10mL of ethyl acetate was added and washed with 5mL of brine. The organic phase was separated and the aqueous phase was extracted 3 times with ethyl acetate. The organic phases were combined and separated by column chromatography with a developing solvent of petroleum ether: ethyl acetate in a ratio of 40:1 to 10:1 to obtain the pure substituted 2-naphthylamine. Figure 1 The reaction synthesis route shown corresponds to the corresponding raw materials I and II, and the experimental results are listed in Table 5:

[0108] Table 5 Non-metal-catalyzed aromatization of substituted 2-naphthone with benzylamine

[0109]

[0110]

[0111] Compound o: N-benzyl-7-methoxy-2-naphthylamine

[0112] 1 H NMR (500MHz, CDCl3) δ7.60(dd,J=9.0,4.3Hz,2H),7.45(d,J=7.5Hz,2H),7.40(t,J=7.6Hz,2H),7.34(d,J=7. 0Hz, 1H), 6.96 (d, J = 2.0Hz, 1H), 6.91 (dd, J = 8.8, 2.4Hz, 1H), 6.81 (d, J = 6.8Hz, 2H), 4.47 (s, 2H), 3.91 (s, 3H). 13 C NMR (126MHz, CDCl3) δ158.2,145.9,139.0,136.4,129.2,128.8,128.7,127.7,127.4,123.1,115.5,114.6,104.6,55.2,48.5ppm.

[0113] Compound p: N-benzyl-6-bromo-2-naphthylamine

[0114] Note: The yield was obtained by replacing the additive N,N-dimethylaniline with ammonium acetate (0.2 mmol).

[0115] 1 H NMR (500MHz, CDCl3) δ7.80(d,J=1.6Hz,1H),7.53(d,J=8.8Hz,1H),7.45(d,J=8.8Hz,1H),7.41–7.35(m, 5H),7.30(t,J=7.2Hz,1H),6.92(dd,J=8.8,2.3Hz,1H),6.77(d,J=2.1Hz,1H),4.42(s,2H),4.25(s,1H). 13 C NMR (125MHz, CDCl3) δ146.0,138.8,133.6,129.6,129.5,128.7,128.6,128.1,127.6,127.6,127.4,118.7,115.1,104.3,48.2ppm.

[0116] Compound q: N-benzyl-1-methyl-2-naphthylamine

[0117] 1 H NMR (400MHz, CDCl3) δ7.89(d,J=8.6Hz,1H),7.69(d,J=8.1Hz,1H),7.61(d,J=8.9Hz,1H),7.45–7.31(m,5H ),7.31–7.25(m,1H),7.21(q,J=4.9Hz,1H),7.07(d,J=8.9Hz,1H),4.53(s,2H),4.16(br,1H),2.44(s,1H); 13 C NMR (100Hz, CDCl3)143.2,139.8,133.3,128.7,128.5,127.6,127.4,127.3,127.2,126.1,122.4,121.6,114.0,112.5,48.7,11.5ppm.

[0118] Compound r: N-(1-phenylethyl)-1-phenyl-2-naphthylamine

[0119] 1H NMR(400MHz, CDCl3)δ7.65(d,J=8.0Hz,1H),7.60–7.56(m,3H),7.49–7.45(m,1H),7.40–7.37(m,2H),7 .30–7.12(m,8H),6.92(d,J=9.0Hz,1H),4.64(q,J=6.7Hz,1H),4.02(s,1H),1.36(d,J=6.8Hz,3H)ppm; 13 C NMR (100MHz, CDCl3) δ145.4,142.1,137.3,133.6,131.4,131.3,129.62,129.57,128.7,127.9,127.8,127.2,127.0,126.2,12 5.9,124.2,121.8,120.1,115.2,53.8,25.1ppm; FTIR(neat)υ3412,2151,1600,1494,1301,702,494; HRMS(ESI)m / z:Calcd.For C 24 H 22 N + :324.1747,Found:324.1747(M+H + ).

[0120] Example 9 Synthesis of N-substituted-2-naphthylamine

[0121]

[0122] R 8 =Any one of L-isoleucine methyl ester, L-serine methyl ester, L-phenylalanine methyl ester, glycine methyl ester, L-valine methyl ester, and L-phenylalanine tert-butyl ester

[0123] Take a 25mL reaction tube, add 14.8mg of tetrabutylammonium iodide, 0.2mmol of tetrahydro-2-naphthalenone, and 0.4mmol of amino acid ester or amino alcohol, MS 150mg, N,N-dimethylaniline 72.8mg, 1,2-dichloroethane 1mL, stirred at 100℃ for 14 hours. After the reaction, 10mL of ethyl acetate was added and washed with 5mL of brine. The organic phase was separated and the aqueous phase was extracted 3 times with ethyl acetate. The organic phases were combined and separated by column chromatography with a developing solvent of petroleum ether: ethyl acetate in a ratio of 40:1 to 10:1 to obtain the pure substituted 2-naphthylamine. Figure 1 The reaction synthesis route shown in the figure takes the corresponding raw materials I and II, and the experimental results are listed in Table 6:

[0124] Table 6 Non-metal-catalyzed aromatization of tetrahydro-2-naphthalenone with amino acid esters or amino alcohols

[0125]

[0126]

[0127] Compound t: N-(2-naphthyl)-L-isoleucine methyl ester

[0128] 1 H NMR (400MHz, CDCl3) δ7.66–7.58(m,3H),7.36–7.32(m,1H),7.22–7.17(m,1H),6.91(dd,J=8.7,2.4Hz,1H),6.80(d,J=2.2Hz,1H),4.33(s ,1H),4.09(d,J=5.3Hz,1H),3.70(s,3H),1.95–1.89(m,1H),1.67(ddd,J=13.5,7.5,4.5Hz,1H),1.39–1.30(m,1H),1.00–0.96(m,6H)ppm; 13 C NMR (100MHz, CDCl3) δ174.2,144.9,135.1,129.2,127.9,127.7,126.5,126.1,122.4,118.3,105.4,61.2,52.0, 38.1,25.9,15.7,11.6ppm; FTIR(neat)υ3390,2962,1732,1629,1522,1190,829,738; HRMS(ESI)m / z:Calcd.For C 17 H 22 NO2 + :272.1645,Found:272.1645(M+H + ).

[0129] Compound u: N-(2-naphthyl)-L-serine methyl ester

[0130] 1 H NMR (400MHz, CDCl3) δ7.69–7.59(m,3H),7.37(ddd,J=8.2,6.9,1.2Hz,1H),7.23(ddd,J=8.0,6.0,1.1Hz,1H),6.95 (dd,J=8.8,2.4Hz,1H),6.83(d,J=2.3Hz,1H),4.33(t,J=4.0Hz,1H),4.01(qd,J=11.1,4.1Hz,2H),3.78(s,3H)ppm;13 C NMR (100MHz, CDCl3) δ172.7,144.2,134.9,129.4,128.2,127.7,126.6,126.2,122.8,118.4,106.0,62 .8,58.5,52.8ppm; FTIR(neat)υ3397,1733,1628,1525,1213,1068,826,468; HRMS(ESI)m / z:Calcd.For C 14 H 16 NO3 + :246.1125,Found:246.1125(M+H + ).

[0131] Compound v: N-(2-naphthyl)-L-phenylalanine tert-butyl ester

[0132] 1 H NMR (400MHz, CDCl3) δ7.66(d,J=8.1Hz,1H),7.60(dd,J=13.3,8.5Hz,2H),7.37–7.33(m,1H),7.31–7.18(m,,6H),6. 88(dd,J=8.8,2.4Hz,1H),6.81(d,J=2.2Hz,1H),4.38(t,J=6.2Hz,2H),3.17(dd,J=6.0,1.7Hz,2H),1.35(s,9H)ppm; 13 C NMR (100MHz, CDCl3) δ172.3,144.3,136.7,135.1,129.7,129.2,128.5,127.9,127.7,127.0,126.4,126.1,122.4,118. 4,105.6,82.0,58.1,38.4,28.1ppm; FTIR(neat)υ2972,1726,1631,1523,1150,836,745,471; HRMS(ESI)m / z:Calcd.For C 23 H 26 NO2 + :348.1958,Found:348.1958(M+H + ).

[0133] Compound w: N-(2-naphthyl)-L-phenylalanine methyl ester

[0134] 1H NMR (400MHz, CDCl3): δ7.67(d,J=8.1Hz,1H),7.63(d,J=8.8Hz,1H),7.60(d,J=8.2Hz,1H),7.39–7.15(m,7H),6.88(d d,J=8.8Hz,2.4Hz,1H),6.80(d,J=2.2Hz,1H),4.52(t,J=6.1Hz,1H),4.34(brs,1H),3.68(s,3H),3.29–3.12(m,2H); 13 C NMR (100MHz, CDCl3): δ173.4,143.9,136.2,134.9,129.2,129.1,128.5,12 7.9,127.6,127.0,126.4,126.0,122.4,118.1,105.5,57.6,52.1,38.3ppm.

[0135] The above content is only for explaining the technical idea of ​​the present invention and cannot be used to limit the protection scope of the present invention. Any changes made on the basis of the technical solution in accordance with the technical idea proposed by the present invention shall fall within the protection scope of the claims of the present invention.

Claims

1. A method for synthesizing an aromatic amine compound without metal participation, characterized in that: After mixing a ketone-containing compound and an amine-containing compound, reacting them in the presence of a non-metallic catalyst and an additive to obtain an aromatic amine compound; The non-metallic catalyst is methyltriphenylphosphine iodide, tetraethylammonium iodide, tetrapropylammonium iodide, benzyltrimethylammonium iodide, tetraheptylammonium iodide or tetrabutylammonium iodide; The additives are selected from N , N -Diisopropylethylamine, 2,6-lutidine, N , N - dimethylaniline, sodium bicarbonate or ammonium acetate; The solvent added to the reaction was 1, 2-dichloroethane; in: The structure of the ketone-containing compound is shown below: ； The ketone-containing compound is specifically selected from 3-methylcyclohex-2-ene-1-one, 3-phenylcyclohex-2-ene-1-one, tetrahydro-2-naphthyl ketone, 、 、 or ; The structure of the prepared aromatic amine compound is shown below: ； The prepared aromatic amine compounds specifically include: N -benzyl-3-methylaniline, N -benzyl-3-phenylaniline, N -benzyl-2-naphthylamine, N -(4-fluorobenzyl)-2-naphthylamine, N -(4-methylbenzyl)-2-naphthylamine, N -(4-methoxybenzyl)-2-naphthylamine, N -(1-phenylethyl)-2-naphthylamine, N -methyl- N -benzyl-2-naphthylamine, N -phenethyl-2-naphthylamine, N -(4-fluorophenethyl)-2-naphthylamine, N -(4-tert-butylphenyl)-2-naphthylamine, N -phenyl-2-naphthylamine, N -(4-nitrophenyl)-2-naphthylamine, N -isopropyl-2-naphthylamine, N -(2-naphthyl)tetrahydropyrrole, 4-(2-naphthyl)morpholine, N -cyclopropyl-2-naphthylamine, N -benzyl-7-methoxy-2-naphthylamine, N -Benzyl-6-bromo-2-naphthylamine, N -benzyl-1-methyl-2-naphthylamine, N -(1-phenylethyl)-1-phenyl-2-naphthylamine, N -(2-naphthyl)- L -Isoleucine methyl ester, N -(2-naphthyl)- L -Serine methyl ester, N -(2-naphthyl)- L -phenylalanine tert-butyl ester and N -(2-naphthyl)- L -phenylalanine methyl ester.

2. The method for synthesizing an aromatic amine compound without metal participation according to claim 1, characterized in that: The reaction temperature is 60~110℃.

3. The method for synthesizing an aromatic amine compound without metal participation according to claim 1, characterized in that: The reaction temperature was 100°C.

4. The method for synthesizing an aromatic amine compound without metal participation according to claim 1, characterized in that: The molar ratio of the ketone-containing compound to the non-metallic catalyst is 4:1 to 2:

1.

5. The method for synthesizing an aromatic amine compound without metal participation according to claim 1, characterized in that: The reaction molar ratio of the ketone-containing compound to the amine-containing compound is 3:1 to 1:

3.

6. The method for synthesizing an aromatic amine compound without metal participation according to claim 1, characterized in that: The concentration of the solvent is 0.5~2 mol / L.

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