Synthesis method of secondary amine compound

Abstract

The invention provides a synthesis method of a secondary amine compound, which comprises the following steps: by taking an aromatic nitro compound and an internal alkyne compound as raw materials, realizing reductive coupling of the aromatic nitro compound and the internal alkyne compound under the action of copper catalysis and silicon hydrogen reduction, and preparing the secondary amine compound under the subsequent reduction action of sodium borohydride. The method has the advantages of cheap and easily available raw materials, simple reaction operation, mild conditions, high efficiency, economy and the like; the problems that catalysts and ligands are expensive and reaction substrates are limited in the process of preparing secondary amine from aromatic nitro compounds and alkyne at present are solved.

Description

Technical Field

[0001] The present invention belongs to the field of organic synthesis, and particularly relates to a method for synthesizing secondary amine compounds.

Background Art

[0002] Secondary amines are an important class of organic nitrogen-containing compounds and are one of the most common organic amine compounds. They are widely used in the fields of fine chemicals, materials science, agrochemistry, and pharmaceutical chemistry (Chem. Soc. Rev. 2013, 42, 9283 - 9283). The traditional methods for preparing secondary amine compounds mainly rely on the further transformation of primary amines, such as the alkylation reaction of primary amines (Chem. Rev. 2010, 110, 1611 - 1641), the reductive amination reaction of amino-carbonyl dehydration (Chem. Rev. 2019, 119, 11857 - 11911), the Buchwald-Hartwig cross-coupling reaction (J. Am. Chem. Soc. 2016, 138, 12053 - 12056; Angew. Chem., Int. Ed. 2017, 56, 13307 - 13309), the Chan-Lam cross-coupling reaction (J. Am. Chem. Soc. 2017, 139, 4769 - 4779; J. Org. Chem. 2021, 86, 9883 - 9897), etc. It is worth noting that the starting primary amines used in these reactions are often prepared from nitro compounds, with a cumbersome route and the primary amines being easily oxidized. Therefore, if secondary amine compounds can be directly prepared from stable and readily available nitro compounds, it will have better step economy and can better save costs.

[0003] Among the numerous reactions for preparing secondary amines from aromatic nitro compounds, the reductive coupling of aromatic nitro compounds with unsaturated hydrocarbon compounds to directly prepare secondary amines is undoubtedly a very practical method because unsaturated hydrocarbons are bulk petrochemical products with rich reserves and are readily available (Science 2015, 348, 886 - 891; Chem2018, 4, 1645 - 1657). In 2024, Szostak et al. first reported the reductive amination reaction of aromatic nitro compounds with terminal alkynes or internal aliphatic alkynes under gold catalysis to prepare secondary amines, which broke the defect that secondary amines cannot be prepared by the reaction of aromatic nitro compounds with alkynes (Nat. Chem. 2024, 16, 2025 - 2035). However, this method still has the following three deficiencies: 1. It requires the use of expensive gold as a reaction catalyst; 2. The N-heterocyclic carbene ligand used in the reaction needs to be prepared through multiple steps of elaborate design, with a cumbersome process and high cost; 3. This reaction has serious substrate defects and cannot convert structurally rich diarylacetylene compounds. These deficiencies have limited the further application of this reaction to a certain extent.

[0004] In view of the deficiencies in the preparation of secondary amines from aromatic nitro compounds and alkynes mentioned above, the present invention aims to develop a reductive coupling reaction of aromatic nitro compounds and internal alkyne compounds, especially diarylacetylene compounds, in the presence of a cheap transition metal copper catalyst to prepare secondary amine compounds. This method has the advantages of cheap and easily available raw materials, simple reaction operation, mild conditions, high efficiency, economy, etc.; it solves the problems of expensive catalysts and ligands and limited reaction substrates in the current preparation of secondary amines from aromatic nitro compounds and alkynes.

Summary of the Invention

[0005] The object of the present invention is to provide a method for preparing secondary amine compounds using aromatic nitro compounds and internal alkyne compounds as raw materials under the conditions of copper catalyst, silane reduction, and subsequent reduction with sodium borohydride.

[0006] To achieve the above object of the invention, the present invention proposes the following technical solutions:

[0007] A method for synthesizing secondary amine compounds, wherein the structure of the secondary amine compounds is shown in Formula I:

[0008]

[0009] wherein the Ar is phenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 4-methoxyphenyl, 3-methoxyphenyl, 2-methoxyphenyl, 4-tert-butylphenyl, 4-biphenyl, 4-thiophenylphenyl, 4-thiomethylphenyl, 4-fluorophenyl, 4-chlorophenyl, 2,3-dimethylphenyl, 2-fluoro-4-methoxyphenyl; Ar 1is phenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 4-methoxyphenyl, 3-methoxyphenyl, 2-methoxyphenyl, 4-tert-butylphenyl, 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 4-trifluoromethylphenyl, 1-naphthyl, 2-naphthyl, 3-thienyl; R is phenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 4-methoxyphenyl, 3-methoxyphenyl, 2-methoxyphenyl, 4-tert-butylphenyl, 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 4-trifluoromethylphenyl, 1-naphthyl, 2-naphthyl, 3-thienyl, cyclopropyl; The synthesis method of compound I is characterized in that an aromatic nitro compound, an internal alkyne, a copper catalyst, an organic phosphine ligand 1,3-bis(diphenylphosphino)propane, a silicon hydride reagent, and an organic solvent are placed in a reaction vessel and mixed, and stirred and reacted at 50-60 °C for 12 hours under a nitrogen atmosphere; After the reaction is completed, the reaction solution is quenched with an aqueous sodium hydroxide solution, extracted with dichloromethane, and then concentrated by distillation under reduced pressure. The concentrated solution is dissolved in methanol and then sodium borohydride is added, and reduced at 0 °C for 12 hours, and then concentrated by distillation under reduced pressure. The crude product is separated by column chromatography to obtain the secondary amine compound shown in formula I.

[0010] In the said synthesis method, the structures of the raw material aromatic nitro compound and the internal alkyne compound are shown in formula II and formula III respectively:

[0011]

[0012] In formula II, Ar is phenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 4-methoxyphenyl, 3-methoxyphenyl, 2-methoxyphenyl, 4-tert-butylphenyl, 4-biphenyl, 4-thiophenylphenyl, 4-thiomethylphenyl, 4-fluorophenyl, 4-chlorophenyl, 2,3-dimethylphenyl, 2-fluoro-4-methoxyphenyl;

[0013] In formula III, Ar 1 is phenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 4-methoxyphenyl, 3-methoxyphenyl, 2-methoxyphenyl, 4-tert-butylphenyl, 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 4-trifluoromethylphenyl, 1-naphthyl, 2-naphthyl, 3-thienyl; R is phenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 4-methoxyphenyl, 3-methoxyphenyl, 2-methoxyphenyl, 4-tert-butylphenyl, 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 4-trifluoromethylphenyl, 1-naphthyl, 2-naphthyl, 3-thienyl, cyclopropyl.

[0014] In the said synthesis method, the copper catalyst is selected from one of copper acetate, copper acetylacetonate, and copper(I) thiophene-2-carboxylate.

[0015] In the synthesis method, the silicon hydride reagent is selected from one of diphenylsilane, phenylsilane, and dimethoxymethylsilane.

[0016] In the synthesis method, the molar ratio of the aromatic nitro compound, the internal alkyne compound, the copper catalyst, the organic phosphine ligand 1,3-bis(diphenylphosphino)propane, the silicon hydride reagent, and sodium borohydride is 1:2:(0.05 - 0.10):0.05:4:2.

[0017] In the synthesis method, the organic solvent is selected from one of toluene, p-xylene, cyclohexane, dioxane, and tetrahydrofuran.

[0018] In the synthesis method, the organic solvent is selected from one of toluene, dioxane, dimethyl sulfoxide, and N,N-dimethylformamide.

[0019] According to the experimental results, the present invention provides a new method for synthesizing secondary amine compounds by reacting aromatic nitro compounds with internal alkyne compounds in the presence of an inexpensive copper transition metal catalyst. This method has the advantages of inexpensive and readily available raw materials, simple reaction operation, mild conditions, high efficiency, and economy; it solves the problems of expensive catalysts and ligands and limited reaction substrates in the current preparation of secondary amines from aromatic nitro compounds and alkynes.

Description of the Drawings

[0020] Attached Figure 1 Shown is the synthesis route diagram of the secondary amine compounds provided by the present invention.

Specific Embodiments

[0021] The following further illustrates the synthesis method described in the present invention in combination with the synthesis examples of the present invention:

[0022] As Figure 1 Shown, the synthesis steps of a secondary amine compound provided by the present invention are as follows: Take the raw material aromatic nitro compound, the internal alkyne compound (molar ratio 200% based on the aromatic nitro compound), as well as the copper catalyst (molar ratio 5% based on the aromatic nitro compound), the organic phosphine ligand 1,3-bis(diphenylphosphino)propane (molar ratio 5% based on the aromatic nitro compound), the silicon hydride reagent (molar ratio 400% based on the aromatic nitro compound), and the organic solvent and place them in a reaction vessel for mixing. Stir and react at 50 - 60 °C for 12 hours under a nitrogen atmosphere; after the reaction is completed, the reaction solution is quenched with an aqueous sodium hydroxide solution, extracted with dichloromethane, and then concentrated by reduced pressure distillation. The concentrated solution is dissolved in methanol and then sodium borohydride (molar ratio 200% based on the aromatic nitro compound) is added, and it is reduced at 0 °C for 12 hours. Subsequently, it is concentrated by reduced pressure distillation, and the crude product is separated by column chromatography to obtain the target secondary amine compound.

[0023] The following further illustrates the present invention in combination with specific preparation examples:

[0024] Synthesis Example 1

[0025] Synthesis of N-(1,2-diphenylethyl)-4-methylaniline

[0026] Add 0.2 mmol of 4-nitrotoluene, 0.4 mmol of diphenylacetylene, copper acetate (10 mol%), 1,3-bis(diphenylphosphino)propane (5 mol%), diphenylsilane (0.8 mmol), and dioxane (0.5 mL) to a reactor, mix them in the reaction vessel, and stir the reaction at 50 °C for 12 hours under a nitrogen atmosphere. After the reaction is completed, the reaction solution is quenched with an aqueous sodium hydroxide solution, extracted with dichloromethane, and then concentrated by distillation under reduced pressure. The concentrated solution is dissolved in methanol and then sodium borohydride (0.4 mmol) is added, and the reduction is carried out at 0 °C for 12 hours. Subsequently, it is concentrated by distillation under reduced pressure, and the crude product is separated by column chromatography to obtain the target product with a yield of 75%. 1 H NMR(400MHz,CDCl3)δ7.31–7.26(m,5H),7.24–7.20(m,3H),7.12(d,J=7.2Hz,2H),6.85(d,J=6.6Hz,2H),6.37(dd,J=8.4,2.0Hz,2H),4.57–4.73(m,1H),3.12(td,J=13.9,5.5,1.3Hz,1H),2.99(td,J=14.0,8.3,1.8Hz,1H),2.16(s,1H).

[0027] Synthesis Example 2

[0028] Synthesis of N-(1,2-diphenylethyl)-3-methylaniline

[0029] Add 0.2 mmol of 3-nitrotoluene, 0.4 mmol of diphenylacetylene, copper(II) 2-thiophenecarboxylate (5 mol%), 1,3-bis(diphenylphosphino)propane (5 mol%), diphenylsilane (0.8 mmol), and dioxane (0.3 mL) to a reactor, mix them in the reaction vessel, and stir the reaction at 60 °C for 12 hours under a nitrogen atmosphere. After the reaction is completed, the reaction solution is quenched with an aqueous sodium hydroxide solution, extracted with dichloromethane, and then concentrated by distillation under reduced pressure. The concentrated solution is dissolved in methanol and then sodium borohydride (0.4 mmol) is added, and the reduction is carried out at 0 °C for 12 hours. Subsequently, it is concentrated by distillation under reduced pressure, and the crude product is separated by column chromatography to obtain the target product with a yield of 72%. 11H NMR (400 MHz, CDCl3) δ 7.30–7.26 (m, 4H), 7.24–7.20 (m, 4H), 7.11 (d, J = 6.5 Hz, 2H), 6.91 (d, J = 7.6 Hz, 1H), 6.43 (s, 1H), 6.30–6.23 (m, 2H), 4.57–4.55 (m, 1H), 4.06 (s, 1H), 3.12–3.09 (m, 1H), 2.99 (dd, J = 11.4, 8.1 Hz, 1H), 2.16 (s, 3H)

[0030] Synthesis Example 3

[0031] Synthesis of N-(1,2-diphenylethyl)-2-methylaniline

[0032] Add 0.2 mmol of 2-nitrotoluene, 0.4 mmol of diphenylacetylene, copper(I) thiophene-2-carboxylate (5 mol%), 1,3-bis(diphenylphosphino)propane (5 mol%), diphenylsilane (0.8 mmol), and dioxane (0.3 mL) to a reaction vessel and mix. Stir the reaction mixture at 60 °C for 12 hours under a nitrogen atmosphere. After the reaction is complete, quench the reaction mixture with an aqueous sodium hydroxide solution, extract with dichloromethane, and then concentrate by distillation under reduced pressure. Dissolve the concentrated solution in methanol and then add sodium borohydride (0.4 mmol). Reduce at 0 °C for 12 hours, and then concentrate by distillation under reduced pressure. The crude product is separated by column chromatography to obtain the target product with a yield of 68%. 1 1H NMR (400 MHz, CDCl3) δ 7.36–7.19 (m, 7H), 7.18–7.05 (m, 3H), 6.99–6.82 (m, 2H), 6.55 (dd, J = 12.8, 5.8 Hz, 1H), 6.27 (dd, J = 11.6, 7.6 Hz, 1H), 4.57 (dd, J = 8.3, 4.9 Hz, 1H), 3.99 (s, 1H), 3.24–3.08 (m, 1H), 2.99 (dd, J = 13.0, 8.8 Hz, 1H), 2.02 (s, 3H).

[0033] Synthesis Example 4

[0034] Synthesis of N-(1,2-diphenylethyl)-4-methoxyaniline

[0035] Add 0.2 mmol of 4-nitroanisole, 0.4 mmol of diphenylacetylene, copper(I) thiophene-2-carboxylate (5 mol%), 1,3-bis(diphenylphosphino)propane (5 mol%), diphenylsilane (0.8 mmol), and dioxane (0.3 mL) into a reaction vessel and mix them. Stir the reaction mixture at 60 °C for 12 hours under a nitrogen atmosphere. After the reaction is completed, quench the reaction solution with an aqueous sodium hydroxide solution, extract it with dichloromethane, and then concentrate it by distillation under reduced pressure. Dissolve the concentrated solution in methanol and then add sodium borohydride (0.4 mmol). Reduce it at 0 °C for 12 hours, and then concentrate it by distillation under reduced pressure. Separate the crude product by column chromatography to obtain the target product with a yield of 73%. 1 H NMR(400MHz,CDCl3)δ7.33–7.26(m,5H),7.25–7.19(m,3H),7.12(d,J=6.9Hz,2H),6.63(t,J=6.2Hz,2H),6.41(t,J=6.2Hz,2H),4.50(dd,J=8.2,5.7Hz,1H),3.65(s,3H),3.11(dd,J=13.9,5.6Hz,1H),2.99(dd,J=13.9,8.3Hz,1H).

[0036] Synthesis Example 5

[0037] Synthesis of N-(1,2-diphenylethyl)-3-methoxyaniline

[0038] Add 0.2 mmol of 3-nitroanisole, 0.4 mmol of diphenylacetylene, copper(I) thiophene-2-carboxylate (5 mol%), 1,3-bis(diphenylphosphino)propane (5 mol%), diphenylsilane (0.8 mmol), and dioxane (0.3 mL) into a reaction vessel and mix them. Stir the reaction mixture at 60 °C for 12 hours under a nitrogen atmosphere. After the reaction is completed, quench the reaction solution with an aqueous sodium hydroxide solution, extract it with dichloromethane, and then concentrate it by distillation under reduced pressure. Dissolve the concentrated solution in methanol and then add sodium borohydride (0.4 mmol). Reduce it at 0 °C for 12 hours, and then concentrate it by distillation under reduced pressure. Separate the crude product by column chromatography to obtain the target product with a yield of 62%. 11H NMR (400 MHz, CDCl3) δ 7.31–7.26 (m, 5H), 7.25–7.19 (m, 3H), 7.11 (d, J = 7.0 Hz, 2H), 6.95 (t, J = 8.1 Hz, 1H), 6.19 (dd, J = 8.1, 2.2 Hz, 1H), 6.08 (dd, J = 8.0, 1.9 Hz, 1H), 6.01 (t, J = 2.2 Hz, 1H), 4.57 (dd, J = 8.1, 5.8 Hz, 1H), 4.15 (s, 1H), 3.64 (s, 3H), 3.12 (dd, J = 14.0, 5.7 Hz, 1H), 3.00 (dd, J = 14.0, 8.2 Hz, 1H).

[0039] Synthesis Example 6

[0040] Synthesis of N-(1,2-diphenylethyl)-4-tert-butylaniline

[0041] Into a reactor were added 0.2 mmol of 4-nitro-tert-butylbenzene, 0.4 mmol of diphenylacetylene, as well as copper(I) thiophene-2-carboxylate (5 mol%), 1,3-bis(diphenylphosphino)propane (5 mol%), diphenylsilane (0.8 mmol), and dioxane (0.3 mL), and they were mixed in the reaction vessel. The mixture was stirred at 60 °C for 12 hours under a nitrogen atmosphere. After the reaction was completed, the reaction solution was quenched with an aqueous sodium hydroxide solution, extracted with dichloromethane, and then concentrated under reduced pressure. The concentrated solution was dissolved in methanol, and then sodium borohydride (0.4 mmol) was added, and the mixture was reduced at 0 °C for 12 hours. Subsequently, it was concentrated under reduced pressure, and the crude product was separated by column chromatography to obtain the target product with a yield of 79%. 1 1H NMR (400 MHz, CDCl3) δ 7.46–7.44 (m, 1H), 7.38–7.27 (m, 5H), 7.23–7.11 (m, 4H), 7.08–7.05 (m, 2H), 6.40 (d, J = 8.7 Hz, 2H), 4.52 (dd, J = 8.5, 5.6 Hz, 1H), 4.04 (s, 1H), 3.10 (dd, J = 14.0, 5.5 Hz, 1H), 2.97 (dd, J = 14.0, 8.5 Hz, 1H), 1.20 (s, 9H).

[0042] Synthesis Example 7

[0043] Synthesis of N-(1,2-diphenylethyl)-4-fluoroaniline

[0044] Add 0.2 mmol of 4-nitrofluorobenzene, 0.4 mmol of diphenylacetylene, copper(I) thiophene-2-carboxylate (5 mol%), 1,3-bis(diphenylphosphino)propane (5 mol%), 0.8 mmol of diphenylsilane, and 0.3 mL of dioxane to a reaction vessel and mix. Stir the reaction mixture at 60 °C for 12 hours under a nitrogen atmosphere. After the reaction is complete, quench the reaction mixture with an aqueous sodium hydroxide solution, extract with dichloromethane, and then concentrate the extract under reduced pressure. Dissolve the concentrated solution in methanol and then add sodium borohydride (0.4 mmol). Reduce the mixture at 0 °C for 12 hours, then concentrate the mixture under reduced pressure. Separate the crude product by column chromatography to obtain the target product with a yield of 64%. 1 H NMR (400 MHz, CDCl3) δ 7.30 (d, J = 4.3 Hz, 4H), 7.28–7.20 (m, 4H), 7.11 (d, J = 6.9 Hz, 2H), 6.84–6.64 (m, 2H), 6.45–6.28 (m, 2H), 4.51 (dd, J = 8.3, 5.6 Hz, 1H), 4.00 (s, 1H), 3.12 (dd, J = 14.0, 5.6 Hz, 1H), 2.98 (dd, J = 14.0, 8.3 Hz, 1H).

[0045] Synthesis Example 8

[0046] Synthesis of N-(1,2-diphenylethyl)-4-chloroaniline

[0047] Add 0.2 mmol of 4-nitrochlorobenzene, 0.4 mmol of diphenylacetylene, copper(II) acetylacetonate (5 mol%), 1,3-bis(diphenylphosphino)propane (5 mol%), 0.8 mmol of diphenylsilane, and 0.3 mL of dioxane to a reaction vessel and mix. Stir the reaction mixture at 60 °C for 12 hours under a nitrogen atmosphere. After the reaction is complete, quench the reaction mixture with an aqueous sodium hydroxide solution, extract with dichloromethane, and then concentrate the extract under reduced pressure. Dissolve the concentrated solution in methanol and then add sodium borohydride (0.4 mmol). Reduce the mixture at 0 °C for 12 hours, then concentrate the mixture under reduced pressure. Separate the crude product by column chromatography to obtain the target product with a yield of 46%. 1 H NMR (400 MHz, CDCl3) δ 7.30–7.21 (m, 8H), 7.13–7.07 (m, 2H), 6.99–6.93 (m, 2H), 6.38–6.32 (m, 2H), 4.53 (dd, J = 8.2, 5.7 Hz, 1H), 4.12 (s, 1H), 3.13 (dd, J = 14.0, 5.7 Hz, 1H), 2.99 (dd, J = 14.0, 8.2 Hz, 1H).

[0048] Synthesis Example 9

[0049] Synthesis of N-(1,2-bis-(4-methylphenyl)ethyl)-4-methylaniline

[0050] Add 0.2 mmol of 4-nitrotoluene, 0.4 mmol of bis-(4-methylphenyl)acetylene, copper(I) thiophene-2-carboxylate (5 mol%), 1,3-bis(diphenylphosphino)propane (5 mol%), diphenylsilane (0.8 mmol), and dioxane (0.3 mL) into a reaction vessel and mix. Stir the reaction at 60 °C for 12 hours under a nitrogen atmosphere. After the reaction is completed, quench the reaction solution with an aqueous sodium hydroxide solution, extract with dichloromethane, and then concentrate by distillation under reduced pressure. Dissolve the concentrated solution in methanol and then add sodium borohydride (0.4 mmol). Reduce at 0 °C for 12 hours, and then concentrate by distillation under reduced pressure. The crude product is separated by column chromatography to obtain the target product with a yield of 78%. 1 H NMR(400MHz,CDCl3)δ7.22–7.19(m,2H),7.12–7.05(m,4H),7.01(d,J=8.0Hz,2H),6.84(d,J=8.2Hz,2H),6.36(d,J=8.4Hz,2H),4.48(dd,J=8.4,5.4Hz,1H),3.96(s,1H),3.07(dd,J=14.1,5.4Hz,1H),2.91(dd,J=14.1,8.5Hz,1H),2.31(d,J=5.1Hz,6H),2.14(s,3H).

[0051] Synthesis Example 10

[0052] Synthesis of N-(1,2-bis-(4-methoxyphenyl)ethyl)-4-methylaniline

[0053] Add 0.2 mmol of 4-nitrotoluene, 0.4 mmol of bis-(4-methoxyphenyl)acetylene, copper(I) thiophene-2-carboxylate (5 mol%), 1,3-bis(diphenylphosphino)propane (5 mol%), diphenylsilane (0.8 mmol), and dioxane (0.3 mL) into a reaction vessel and mix. Stir the reaction at 60 °C for 12 hours under a nitrogen atmosphere. After the reaction is completed, quench the reaction solution with an aqueous sodium hydroxide solution, extract with dichloromethane, and then concentrate by distillation under reduced pressure. Dissolve the concentrated solution in methanol and then add sodium borohydride (0.4 mmol). Reduce at 0 °C for 12 hours, and then concentrate by distillation under reduced pressure. The crude product is separated by column chromatography to obtain the target product with a yield of 78%. 11H NMR (400 MHz, CDCl3) δ 7.25–7.19 (m, 2H), 7.00 (t, J = 5.7 Hz, 2H), 6.93–6.74 (m, 6H), 6.48–6.32 (m, 2H), 4.45 (dd, J = 7.8, 6.0 Hz, 1H), 3.78 (d, J = 1.6 Hz, 6H), 3.02 (dd, J = 14.0, 5.9 Hz, 1H), 2.92 (dd, J = 14.0, 7.9 Hz, 1H), 2.16 (s, 3H).

[0054] Synthesis Example 11

[0055] Synthesis of N-(1,2-bis-(4-bromophenyl)ethyl)-4-methylaniline

[0056] 0.2 mmol of 4-nitrotoluene, 0.4 mmol of bis-(4-bromophenyl)acetylene, copper(I) thiophene-2-carboxylate (5 mol%), 1,3-bis(diphenylphosphino)propane (5 mol%), diphenylsilane (0.8 mmol), and dioxane (0.3 mL) were added to a reaction vessel and mixed. The mixture was stirred at 60 °C for 12 h under a nitrogen atmosphere. After the reaction was completed, the reaction solution was quenched with an aqueous sodium hydroxide solution, extracted with dichloromethane, and then concentrated under reduced pressure. The concentrated solution was dissolved in methanol, and then sodium borohydride (0.4 mmol) was added. The mixture was reduced at 0 °C for 12 h, and then concentrated under reduced pressure. The crude product was separated by column chromatography to obtain the target product with a yield of 63%. 1 1H NMR (400 MHz, CDCl3) δ 7.44–7.34 (m, 4H), 7.14 (d, J = 8.4 Hz, 2H), 6.93 (d, J = 8.3 Hz, 2H), 6.87 (d, J = 8.2 Hz, 2H), 6.35 (d, J = 8.4 Hz, 2H), 4.48 (t, J = 6.9 Hz, 1H), 3.11–2.90 (m, 2H), 2.17 (s, 3H).

[0057] It should be noted that the above examples do not limit the scope of the present invention. For those of ordinary skill in the art, without departing from the concept of the present invention, several modifications and improvements can be made, and these all fall within the scope of the present invention's protection.

Claims

1. A method for synthesizing a secondary amine compound, comprising the following steps: The raw materials of aromatic nitro compound, internal alkyne compound, copper catalyst, organic phosphine ligand 1,3-bis(diphenylphosphinopropane), silicon hydrogen reagent and organic solvent are placed in a reaction container and mixed, and stirred at 50-60° C. for 12 hours under nitrogen environment; after the reaction, the reaction solution is quenched with sodium hydroxide aqueous solution, extracted with dichloromethane and concentrated by vacuum distillation, the concentrated solution is dissolved in methanol and then sodium borohydride is added, reduced at 0° C. for 12 hours, and then concentrated by vacuum distillation, and the crude product is separated by column chromatography to obtain a secondary amine compound as shown in Formula I: In the formula I, Ar is phenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 4-methoxyphenyl, 3-methoxyphenyl, 2-methoxyphenyl, 4-tert-butylphenyl, 4-biphenyl, 4-thiophenylphenyl, 4-thiomethylphenyl, 4-fluorophenyl, 4-chlorophenyl, 2,3-dimethylphenyl, 2-fluoro-4-methoxyphenyl; Ar 1 is phenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 4-methoxyphenyl, 3-methoxyphenyl, 2-methoxyphenyl, 4-tert-butylphenyl, 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 4-trifluoromethylphenyl, 1-naphthyl, 2-naphthyl, 3-thienyl; R is phenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 4-methoxyphenyl, 3-methoxyphenyl, 2-methoxyphenyl, 4-tert-butylphenyl, 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 4-trifluoromethylphenyl, 1-naphthyl, 2-naphthyl, 3-thienyl, or cyclopropyl.

2. The method for synthesizing secondary amine compounds according to claim 1, characterized in that: The structures of the raw material aromatic nitro compound and the internal alkyne compound used in the synthesis method are shown in Formula II and Formula III respectively: In the formula II, Ar is phenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 4-methoxyphenyl, 3-methoxyphenyl, 2-methoxyphenyl, 4-tert-butylphenyl, 4-biphenyl, 4-thiophenylphenyl, 4-thiomethylphenyl, 4-fluorophenyl, 4-chlorophenyl, 2,3-dimethylphenyl, 2-fluoro-4-methoxyphenyl; In the formula III, Ar 1 is phenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 4-methoxyphenyl, 3-methoxyphenyl, 2-methoxyphenyl, 4-tert-butylphenyl, 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 4-trifluoromethylphenyl, 1-naphthyl, 2-naphthyl, 3-thienyl; R is phenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 4-methoxyphenyl, 3-methoxyphenyl, 2-methoxyphenyl, 4-tert-butylphenyl, 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 4-trifluoromethylphenyl, 1-naphthyl, 2-naphthyl, 3-thienyl, or cyclopropyl.

3. The method for synthesizing secondary amine compounds according to claim 1, characterized in that: The copper catalyst is selected from one of copper acetate, copper acetylacetonate and cuprous thiophene-2-carboxylate.

4. The method for synthesizing secondary amine compounds according to claim 1, characterized in that: The silicon hydrogen reagent is selected from one of diphenylsilane, phenylsilane and dimethoxymethylsilane.

5. The method for synthesizing secondary amine compounds according to claim 1, characterized in that: The molar ratio of the aromatic nitro compound, the internal alkyne compound, the copper catalyst, the organic phosphine ligand 1,3-bis(diphenylphosphino)propane, the silicon hydride reagent and the sodium borohydride is 1:2:(0.05-0.10):0.05:4:

2.

6. The method for synthesizing secondary amine compounds according to claim 1, characterized in that: The organic solvent is selected from toluene, dioxane, dimethyl sulfoxide, and N,N-dimethylformamide.

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