A preparation method of N,N-dimethyl-1-naphthylamine compound

Abstract

The present invention belongs to the field of fine chemicals and related chemical technologies, and provides a method for preparing N, N-dimethyl-1-naphthylamine compounds. Using 1-chloromethylnaphthalene and its derivatives as raw materials, in the presence of a catalyst, in the presence of a base and an additive, under anhydrous organic solvent conditions, reacting at 80° C. for 2 hours, N, N-dimethyl-1-naphthylamine compounds can be obtained. The beneficial effects of the present invention are that the preparation method has mild reaction conditions, simple experimental operation, and high product yield; the N, N-dimethyl-1-naphthylamine compounds prepared by the method can be further functionalized to obtain various different compounds, which are applied to the development and research of organic functional materials, bioactive molecules, and fine chemicals.

Description

Technical Field

[0001] The invention belongs to the field of fine chemicals and related chemical technologies, and provides a method for preparing an efficient N,N-dimethyl-1-naphthylamine compound. Background Art

[0002] 1-(N,N-dimethylamino)-4-substituted naphthalene is a representative structural unit in organic functional materials, ligands and bioactive molecules, in which N,N-dimethylamino is crucial to its functionality. Therefore, it is extremely important to develop a simple method to connect dimethylamino to the naphthalene ring. The reported preparation methods of N,N-dimethyl-1-naphthylamine are divided into three types according to the type of reaction mode. The first one is the N-methylation reaction of aromatic primary amines (Jiang X., Wang C., Wei Y., Xue D., Liu Z., and Xiao J. Chem. Eur. J., 2014, 20, 58–63), which uses aromatic primary amines as substrates and dimethylating agents such as methyl halide, methanol, and dimethyl sulfoxide as methyl sources to obtain N,N-dimethyl aromatic amine compounds. However, the reaction conditions are harsh and N-methyl aromatic amine compounds are easily obtained as byproducts. The second is the coupling reaction of aromatic halides with N,N-dimethylamination reagents (Wheaton CA, Bow JJ, and Stradiotto M. Organometallics 2013, 32, 6148-6161), which uses aromatic halides as substrates, selects dimethylamine, dimethylamine solution, dimethylamine hydrochloride, etc. as dimethylamination reagents, and generates N,N-dimethyl aromatic amine compounds under transition metal catalyst conditions. However, this type of reaction often requires the use of complex ligands and is difficult to use in industrial production. The third is the direct C–H amination reaction of aromatic compounds (Ruffoni A., Juliá F., Svejstrup TD, McMillan A.J., Douglas JJ and Leonori D. Nat. Chem., 2019, 11, 426-433), which is a method for directly coupling aromatic compounds with dimethyl amination reagents to obtain N,N-dimethyl aromatic amines. Since this method has complicated steps, it has not been widely used in the industrial field.

[0003] Recently, researchers have discovered that naphthylbenzylamine compounds can be obtained by reacting N,N-dimethylformamide as a dimethylamination reagent with naphthylbenzyl chloride compounds under alkaline conditions (Chen WX, Zhang CYand Lu JMJ Chem. Res., 2013, 37, 611-614). However, this type of reaction occurs at the benzyl position of the aromatic ring. The preparation method of using N,N-dimethylformamide as a dimethylamination reagent and reacting with naphthylbenzyl chloride compounds on the aromatic ring to obtain N,N-dimethyl-1-naphthylamine compounds has not been reported. Summary of the invention

[0004] The present invention provides a novel preparation method of N,N-dimethyl-1-naphthylamine compounds, which uses tetrakis(triphenylphosphine)palladium as a catalyst to achieve remote C–H bond dimethylation of 1-chloromethylnaphthalene and its derivatives. The method has mild reaction conditions, simple experimental operation, good substrate compatibility and high reaction yield.

[0005] The technical solution of the present invention:

[0006] An efficient preparation method of N,N-dimethyl-1-naphthylamine compounds, using 1-chloromethylnaphthalene and its derivatives as raw materials, using N,N-dimethylformamide as a dimethylamination reagent, reacting at 80°C for 2 hours in an anhydrous organic solvent in the presence of a palladium catalyst, a base, and an additive, to obtain the corresponding N,N-dimethyl-1-naphthylamine compounds, the synthesis route is as follows:

[0007]

[0008] In the formula, R is selected from aryl and alkyl;

[0009] The molar ratio of 1-chloromethylnaphthalene and its derivatives to the palladium catalyst is 1:0.01 to 1:0.1;

[0010] The molar ratio of 1-chloromethylnaphthalene and its derivatives to the base is 1:1 to 1:4;

[0011] The molar ratio of 1-chloromethylnaphthalene and its derivatives to the additive is 1:0.01 to 1:0.1;

[0012] The molar ratio of 1-chloromethylnaphthalene and its derivatives to N,N-dimethylformamide is 1:1 to 1:4;

[0013] The molar concentration of 1-chloromethylnaphthalene and its derivatives in the reaction system is 0.1 mmol / mL.

[0014] The palladium catalyst is one or a mixture of two or more of tetrakis(triphenylphosphine)palladium, tris(dibenzylideneacetone)dipalladium, palladium acetate, palladium acetylacetonate, palladium pivalate, palladium dibromide, ditriphenylphosphine palladium diacetate, and tetraacetonitrile palladium tetrafluoroborate, preferably tetrakis(triphenylphosphine)palladium, palladium acetylacetonate, and tris(dibenzylideneacetone)dipalladium.

[0015] The organic solvent is one or a mixture of two or more of N,N-dimethylformamide, dimethyl sulfoxide, 1,4-dioxane, tetrahydrofuran, 2-methyltetrahydrofuran, N-methylpyrrolidone, acetonitrile, ether, ethylene glycol dimethyl ether and toluene, preferably tetrahydrofuran, 2-methyltetrahydrofuran and ethylene glycol dimethyl ether.

[0016] The additive is one of water, methanol, ethanol and isopropanol or a mixture of two or more thereof, preferably water, methanol and ethanol.

[0017] The base is one or a mixture of two or more of cesium carbonate, sodium carbonate, potassium phosphate, sodium hydride, potassium tert-butoxide, lithium tert-butoxide, sodium tert-butoxide, sodium hydroxide, and potassium hydroxide, preferably potassium tert-butoxide, sodium tert-butoxide, and sodium hydroxide.

[0018] Separation methods include recrystallization, column chromatography, and the like.

[0019] The solvents used in the recrystallization method include petroleum ether, dichloromethane, ethyl acetate, acetone, ether, n-hexane, and chloroform.

[0020] When the product is separated by column chromatography, silica gel or neutral alumina is used as the stationary phase, and the developing agent is generally a mixed solvent of polar and non-polar solvents, such as ethyl acetate-petroleum ether, dichloromethane-petroleum ether, ethyl acetate-n-hexane, and methanol-petroleum ether.

[0021] The beneficial effects of the present invention are that the preparation method has mild reaction conditions, simple experimental operation and high product yield; the N,N-dimethyl-1-naphthylamine compound synthesized by the method can be further functionalized to obtain various compounds, which are applied to the development and research of organic functional materials, bioactive molecules and fine chemicals. BRIEF DESCRIPTION OF THE DRAWINGS

[0022] Figure 1 is the 4-benzyl-N,N-dimethylnaphthalene-1-amine in Example 1 1 H NMR spectrum.

[0023] Figure 2 is the 4-benzyl-N,N-dimethylnaphthalene-1-amine in Example 1 13 C NMR spectrum.

[0024] Figure 3is the N,N-dimethyl-4-(4-methylbenzyl)naphthalene-1-amine in Example 2 1 H NMR spectrum.

[0025] Figure 4 is the N,N-dimethyl-4-(4-methylbenzyl)naphthalene-1-amine in Example 2 13 C NMR spectrum.

[0026] Figure 5 is the N,N-dimethyl-4-(2-methylbenzyl)naphthalene-1-amine in Example 3 1 H NMR spectrum.

[0027] Figure 6 is the N,N-dimethyl-4-(2-methylbenzyl)naphthalene-1-amine in Example 3 13 C NMR spectrum.

[0028] Figure 7 is the 4-(4-fluorobenzyl)-N,N-dimethylnaphthalene-1-amine in Example 4 1 H NMR spectrum.

[0029] Figure 8 is the 4-(4-fluorobenzyl)-N,N-dimethylnaphthalene-1-amine in Example 4 13 C NMR spectrum.

[0030] Fig. 9 is the 4-(4-chlorobenzyl)-N,N-dimethylnaphthalene-1-amine in Example 5 1 H NMR spectrum.

[0031] Fig.10 is the 4-(4-chlorobenzyl)-N,N-dimethylnaphthalene-1-amine in Example 5 13 C NMR spectrum.

[0032] Fig.11 is the 4-ethyl-N,N-dimethylnaphthalene-1-amine in Example 6 1 H NMR spectrum.

[0033] Fig.12 is the 4-ethyl-N,N-dimethylnaphthalene-1-amine in Example 6 13 C NMR spectrum.

[0034] Fig.13 is the 4-propyl-N,N-dimethyl-naphthalene-1-amine in Example 7 1 H NMR spectrum.

[0035] Fig.14 is the 4-propyl-N,N-dimethyl-naphthalene-1-amine in Example 7 13 C NMR spectrum.

[0036] Fig.15 is the 4-butyl-N,N-dimethylnaphthalene-1-amine in Example 8 1 H NMR spectrum.

[0037] Fig.16 is the 4-butyl-N,N-dimethylnaphthalene-1-amine in Example 8 13 C NMR spectrum. DETAILED DESCRIPTION

[0038] The preparation method of the N,N-dimethyl-1-naphthylamine compound of the present invention has the advantages of mild reaction conditions, simple experimental operation, good substrate compatibility, high reaction yield, etc.

[0039] The present invention is further described below in conjunction with specific embodiments. These embodiments are only used to illustrate the present invention and are not used to limit the scope of the present invention. Simple replacement or improvement made by those skilled in the art to the present invention belongs to the technical solution protected by the present invention.

[0040] Example 1: Synthesis of 4-benzyl-N,N-dimethylnaphthalene-1-amine

[0041] 1-[Chloro(phenyl)methyl]naphthalene (0.076 g, 0.3 mmol), tetrakis(triphenylphosphine)palladium (0.017 g, 0.015 mmol), sodium tert-butoxide (0.115 g, 1.2 mmol), N,N-dimethylformamide (69.24 μL, 0.9 mmol) and water (54 μL, 0.003 mmol) were added to a 25 mL reactor in sequence, and 3.0 mL of anhydrous 2-methyltetrahydrofuran was added. The mixture was stirred for 2 hours at 80°C under nitrogen. Column chromatography (silica gel, 200-300 mesh; developing solvent: petroleum ether / ethyl acetate = 100:1) gave 0.075 g of 4-benzyl-N,N-dimethylnaphthalene-1-amine, with a yield of 95%.

[0042]

[0043] 4-Benzyl-N,N-dimethylnaphthalen-1-amine: pale yellow solid. 1 H NMR (400MHz, CDCl3) δ8.28 (dd, J=8.3, 1.6Hz, 1H), 7.92 (dd, J=8.2, 1.5Hz, 1H), 7.4 6–7.37(m,2H),7.25–7.09(m,6H),6.97(d,J=7.6Hz,1H),4.33(s,2H),2.83(s,6H). 13C NMR (101MHz, CDCl3) δ150.1,141.1,133.3,131.3,129.3,128.8,128.6,128.5, 127.3,126.1,125.9,125.0,124.9,124.8,113.8,77.5,77.2,76.8,45.5,38.9.

[0044] Example 2: Synthesis of N,N-dimethyl-4-(4-methylbenzyl)naphthalene-1-amine

[0045] The operation was the same as in Example 1, and 0.078 g of N,N-dimethyl-4-(4-methylbenzyl)naphthalene-1-amine was obtained from 4-(chloro(p-tolyl)methyl)naphthalene. The yield was 94%.

[0046]

[0047] N,N-Dimethyl-4-(4-methylbenzyl)naphthalen-1-amine: brown solid. 1 H NMR(400MHz, CDCl3)δ8.28(dd,J=7.9,1.7Hz,1H),7.99–7.87(m,1H),7.52–7.40(m,2H),7.28– 7.15(m,1H),7.12–7.03(m,4H),7.01(d,J=7.6Hz,1H),4.33(s,2H),2.87(s,6H),2.29(s,3H). 13 C NMR (101MHz, CDCl3) δ137.9,135.4,133.2,131.5,129.3,129.1,128.6,127 .1,125.8,124.9,124.8,124.7,113.7,77.4,77.1,76.7,45.4,38.4,21.0.

[0048] Example 3: Synthesis of N,N-dimethyl-4-(2-methylbenzyl)naphthalene-1-amine

[0049] The operation was the same as in Example 1, and 0.072 g of N,N-dimethyl-4-(2-methylbenzyl)naphthalene-1-amine was obtained from 2-(chloro(o-tolyl)methyl)naphthalene with a yield of 87%.

[0050]

[0051] N,N-Dimethyl-4-(2-methylbenzyl)naphthalene-1-amine: brown oily liquid. 1H NMR(400MHz, CDCl3)δ8.31(dd,J=7.9,1.8Hz,1H),7.97–7.90(m,1H),7.54–7.41(m,2H),7.22(d,J=7.7H z,1H),7.18–7.13(m,1H),7.09–7.05(m,1H),6.99–6.87(m,3H),4.32(s,2H),2.87(s,6H),2.32(s,3H). 13 C NMR (101MHz, CDCl3) δ138.8,136.7,133.4,130.7,130.1,129.7,129.1,126.4,126 .3,126.1,125.9,125.0,124.8,124.4,113.9,77.4,77.1,76.8,45.5,36.0,19.7.

[0052] Example 4: Synthesis of 4-(4-fluorobenzyl)-N,N-dimethylnaphthalene-1-amine

[0053] The operation was the same as in Example 1, and 0.075 g of 4-(4-fluorobenzyl)-N,N-dimethylnaphthalene-1-amine was obtained from 1-(chloro(4-fluorophenyl)methyl)naphthalene. The yield was 89%.

[0054]

[0055] 4-(4-Fluorobenzyl)-N,N-dimethylnaphthalen-1-amine: brown oily liquid. 1 H NMR (400MHz, CDCl3) δ8.29 (dd, J=8.2, 1.7Hz, 1H), 7.89 (dd, J=8.0, 1.6Hz, 1H), 7.47–7.35 (m ,2H),7.18–7.07(m,3H),7.00(d,J=7.6Hz,1H),6.97–6.87(m,2H),4.31(s,2H),2.86(s,6H). 13 C NMR (101MHz, CDCl3) δ161.4 (d, J = 239.5Hz), 160.2, 150.2, 136.7 (d, J = 3.3Hz), 133.2, 131.0, 130.1 (d, J = 7. 8Hz),129.4,127.2,125.9,125.0,124.9,124.8,115.2(d,J=21.3Hz),113.7,77.4,77.1,76.8,45.4,38.1.

[0056] Example 5: Synthesis of 4-(4-chlorobenzyl)-N,N-dimethylnaphthalene-1-amine

[0057] The operation was the same as in Example 1, and 0.074 g of 4-(4-chlorobenzyl)-N,N-dimethylnaphthalene-1-amine was obtained from 1-(chloro(4-chlorophenyl)methyl)naphthalene with a yield of 84%.

[0058]

[0059] 4-(4-Chlorobenzyl)-N,N-dimethylnaphthalen-1-amine: brown oily liquid. 1 H NMR (400MHz, CDCl3) δ8.32–8.25(m,1H),7.90–7.83(m,1H),7.49–7.34(m,2H),7.21–7.03(m,6H),7.00(d,J=7.6Hz,1H),4.31(s,2H),2.87(s,6H). 13 C NMR (151MHz, CDCl3) δ150.3,139.6,133.1,131.7,130.6,130.1,129.4,128 .5,127.3,125.9,125.0,124.9,124.6,113.7,77.3,77.1,76.9,45.4,38.3.

[0060] Example 6: Synthesis of 4-ethyl-N,N-dimethylnaphthalene-1-amine

[0061] 1-(1-chloroethyl)naphthalene (0.057 g, 0.3 mmol), tetrakis(triphenylphosphine)palladium (0.017 g, 0.015 mmol), sodium tert-butoxide (0.115 g, 1.2 mmol) and water (54 μL, 0.003 mmol) were added to a 25 mL reactor in sequence, and 3.0 mL of anhydrous N,N-dimethylformamide was added, and stirred for 1 h at 80°C under nitrogen. Column chromatography (silica gel, 200-300 mesh; developing solvent: petroleum ether / ethyl acetate = 100:1) was used to separate 0.053 g of 4-ethyl-N,N-dimethylnaphthalene-1-amine, with a yield of 88%.

[0062]

[0063] 4-Ethyl-N,N-dimethylnaphthalen-1-amine: brown oily liquid. 1 H NMR (400MHz, CDCl3) δ8.32–8.25(m,1H),8.04–7.99(m,1H),7.53–7.42(m,2H),7.24(d,J= 7.6Hz,1H),7.01(d,J=7.6Hz,1H),3.10–2.98(m,2H),2.86(s,6H),1.35(t,J=7.5Hz,3H). 13CNMR (101MHz, CDCl3) δ149.4,134.9,132.9,129.2,125.6,124.8,124.7,124.2,113.9,77.4,77.1,76.8,45.4,25.7,15.1.

[0064] Example 7: Synthesis of 4-propyl-N,N-dimethylnaphthalene-1-amine

[0065] The operation was the same as that in Example 6, and 0.055 g of 4-propyl-N,N-dimethylnaphthalene-1-amine was obtained from 1-(1-chloropropyl)naphthalene. The yield was 87%.

[0066]

[0067] 4-Propyl-N,N-dimethylnaphthalen-1-amine: brown oily liquid. 1 H NMR (400MHz, CDCl3) δ8.31–8.27(m,1H),8.07–7.95(m,1H),7.52–7.45(m,2H),7.23(d,J=7.6Hz,1H),7. 01(d,J=7.6Hz,1H),2.98(dd,J=8.7,6.8Hz,2H),2.86(s,6H),1.81–1.71(m,2H),1.02(t,J=7.3Hz,3H). 13 C NMR (101MHz, CDCl3) δ133.0,129.1,125.7,125.6,124.8,124.7,124.4,113.9,77.4,77.1,76.7,45.5,35.0,24.0,14.3.

[0068] Example 8: Synthesis of 4-butyl-N,N-dimethylnaphthalene-1-amine

[0069] The operation was the same as that in Example 6, and 0.059 g of 4-butyl-N,N-dimethylnaphthalene-1-amine was obtained from 1-(1-chlorobutyl)naphthalene. The yield was 86%.

[0070]

[0071] 4-Butyl-N,N-dimethylnaphthalen-1-amine: brown oily liquid. 1H NMR(400MHz,CDCl3)δ8.33–8.24(m,1H),8.06–7.96(m,1H),7.52–7.42(m,2H),7.22(d,J=7.6Hz,1H),7.00(d,J=7.6Hz,1H),3.06–2.94(m,2H),2.85(s,6H),1.75–1.67(m,2H),1.49–1.40(m,2H),0.96(t,J=7.3Hz,3H). 13 C NMR(101MHz,CDCl3)δ149.3,133.7,133.0,129.3,125.7,125.5,124.8,124.4,113.8,77.4,77.1,76.8,45.4,33.1,32.7,23.0,14.1。

Claims

1. A method for preparing an N,N-dimethyl-1-naphthylamine compound, characterized in that: Using 1-chloromethylnaphthalene derivatives as raw materials and N,N-dimethylformamide as dimethyl amination reagent, in the presence of palladium catalyst, base, and additives, in an anhydrous organic solvent, react at 80°C for 2 hours to obtain the corresponding N,N-dimethyl-1-naphthylamine compound. The synthetic route is as follows: In the formula, R is selected from aryl and alkyl; The molar ratio of the 1-chloromethylnaphthalene derivative to the palladium catalyst is 1:0.01 to 1:0.1; The molar ratio of the derivative of 1-chloromethylnaphthalene to the base is 1:1 to 1:4; The molar ratio of the derivative of 1-chloromethylnaphthalene to the additive is 1:0.01 to 1:0.1; The molar ratio of the derivative of 1-chloromethylnaphthalene to N,N-dimethylformamide is 1:1 to 1:4; The molar concentration of the 1-chloromethylnaphthalene derivative in the reaction system is 0.1 mmol / mL; The palladium catalyst is one or a mixture of two or more of tetrakis(triphenylphosphine)palladium, tris(dibenzylideneacetone)dipalladium, palladium acetate, palladium acetylacetonate, palladium pivalate, palladium dibromide, ditriphenylphosphine palladium diacetate, and tetraacetonitrile palladium tetrafluoroborate; The additive is water.

2. The preparation method according to claim 1, characterized in that: The organic solvent is one or a mixture of two or more of N,N-dimethylformamide, dimethyl sulfoxide, 1,4-dioxane, tetrahydrofuran, 2-methyltetrahydrofuran, N-methylpyrrolidone, acetonitrile, ether, ethylene glycol dimethyl ether and toluene.

3. The preparation method according to claim 1, characterized in that: The base is one or a mixture of two or more of cesium carbonate, sodium carbonate, potassium phosphate, sodium hydride, potassium tert-butoxide, lithium tert-butoxide, sodium tert-butoxide, sodium hydroxide and potassium hydroxide.

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