Preparation method of 2-(3-methyl-1-methylene butyl) aniline

Abstract

The invention discloses a preparation method of 2-(3-methyl-1-methylene butyl) aniline, which comprises the following specific implementation process: under the action of palladium and phosphine composite catalysis, organic alkali and organic solvent, o-iodoaniline and 4-methyl-1-pentene react to synthesize a penflufen key intermediate 2-(3-methyl-1-methylene butyl) aniline, the method disclosed by the invention has the characteristics of good reaction selectivity, mild reaction conditions, high reaction conversion rate, low reaction cost and the like.

Description

Technical Field

[0001] The invention belongs to the technical field of chemical organic synthesis, and specifically relates to a preparation method of 2-(3-methyl-1-methylenebutyl)aniline. Background Art

[0002] Fluopicolide is a pyrazoleamide fungicide developed by Bayer and patented in 2006. It is mainly used for seed treatment and has good fungicidal activity against a variety of plant pathogenic fungi.

[0003] The synthesis method of the key intermediate 2-(3-methyl-1-methylenebutyl)aniline of trifloxystrobin is mainly as described in patents CN1178791A, CN1338452A, and CN1067063, using 2-aminoacetophenone as a raw material, and reacting with isobutylmagnesium chloride to obtain the intermediate 2-(2-aminophenyl)-4-methyl-2-pentanol, and then dehydrating and hydrogenating to obtain 2-(3-methyl-1-methylenebutyl)aniline. This method uses a Grignard reagent, which is relatively expensive and has harsh reaction conditions, which is not conducive to industrial production.

[0004] . Summary of the invention

[0005] In view of the problems existing in the prior art, the object of the present invention is to provide a method for preparing 2-(3-methyl-1-methylenebutyl)aniline with mild reaction conditions and low reaction cost.

[0006] The specific technical solutions are as follows: The invention discloses a method for preparing 2-(3-methyl-1-methylenebutyl)aniline. Under the action of a palladium phosphine composite catalyst, an organic base and an organic solvent, o-iodoaniline reacts with 4-methyl-1-pentene to generate 2-(3-methyl-1-methylenebutyl)aniline.

[0007] Further, the palladium phosphine composite catalyst is composed of bis(dibenzylideneacetone palladium) or palladium acetate coordinated with a trivalent phosphine compound, wherein the trivalent phosphine compound is triisopropylphosphine fluoroborate, tricyclohexylphosphine fluoroborate, tri-tert-butylphosphine fluoroborate, dicyclohexylbiphenylphosphine borate, di-tert-butylmethylphosphine fluoroborate, dicyclohexylphenylphosphine, tricyclohexylphosphine, diphenylcyclohexylphosphine, tributylphosphine, n-butyldi(1-adamantyl)phosphine, di-n-butyl(1-adamantyl)phosphine, tri(p-tolyl)phosphine, triphenylphosphine, tri(pentafluorophenyl)phosphine, tri(tetramethoxyphenyl)phosphine, tri(4-bromophenyl)phosphine or tri(3.5-bis(trifluoromethyl)phenyl)phosphine, preferably dicyclohexylbiphenylphosphine borate or n-butyldi(1-adamantyl)phosphine, and the molar ratio of bis(dibenzylideneacetone palladium) or palladium acetate to the trivalent phosphine compound is 1:2~6, preferably 1:5.

[0008] Furthermore, the organic base is N,N-diisopropylethylamine, diethylamine or triethylamine.

[0009] Further, the reaction is carried out in an organic solvent, and the organic solvent is N,N-dimethylformamide, N,N-dimethylacetamide, toluene, tetrahydrofuran, dimethyl sulfoxide, 2-methyltetrahydrofuran, N-methylpyrrolidone or acetonitrile, preferably acetonitrile or dimethyl sulfoxide.

[0010] Furthermore, the molar ratio of o-iodoaniline to the palladium phosphine composite catalyst is 1:0.01-0.06, preferably 1:0.025.

[0011] Furthermore, the molar ratio of o-iodoaniline to 4-methyl-1-pentene is 1:1-6, preferably 1:5.

[0012] Furthermore, the molar ratio of o-iodoaniline to the organic base is 1:2-4, preferably 1:2.

[0013] Furthermore, the reaction temperature is 60-110°C, preferably 85°C.

[0014] The beneficial effects of the present invention are: Compared with the existing methods, the preparation method of the present invention has the characteristics of good reaction selectivity, mild reaction conditions, high reaction conversion rate, low reaction cost and the like. DETAILED DESCRIPTION

[0015] The present invention is further described below in conjunction with specific examples, but the protection scope of the present invention is not limited thereto.

[0016] Reaction equation of the present invention is as follows:

[0017] Example 1: o-Iodoaniline (1 mmol, 219 mg), palladium acetate (0.06 mmol, 13 mg) and triisopropylphosphine fluoroborate (0.264 mmol, 65 mg) were added to a 15 ml pressure bottle, protected by nitrogen, sealed, and then injected with a syringe. A mixed solution of N,N-diisopropylethylamine (2 mmol, 258 mg), 2 ml of acetonitrile and 4-methyl-1-pentene (5 mmol, 420 mg) was added. The stopcock was tightened, the temperature was raised to 85°C and the reaction was carried out for 16 h. Thin layer chromatography was used for separation, and the developing solvent was PE:EA=20:1 to obtain 115 mg of 2-(3-methyl-1-methylenebutyl)aniline with a yield of 66%. 1H NMR (400 MHz, CHD3) δ 7.16 – 7.01 (m, 2H), 6.84 – 6.68 (m, 2H), 5.31 (dt, J = 2.5, 1.3 Hz, 1H), 5.17 (d, J = 2.4 Hz, 1H), 3.86 (s, 2H), 2.35 (dd, J = 7.1, 1.3 Hz, 2H), 1.69 (dq, J = 13.5, 6.7Hz, 1H), 0.97 (d, J = 6.8 Hz, 6H). Example 2: o-Iodoaniline (1 mmol, 219 mg), palladium acetate (0.06 mmol, 13 mg) and tri-tert-butylphosphine fluoroborate (0.264 mmol, 77 mg) were added to a 15 ml pressure bottle, protected by nitrogen, sealed, and then injected with a syringe. A mixed solution of N,N-diisopropylethylamine (2 mmol, 258 mg), 2 ml of acetonitrile and 4-methyl-1-pentene (5 mmol, 420 mg) was added. The stopcock was tightened, the temperature was raised to 85°C, the reaction was carried out for 16 h, and thin layer chromatography was used for separation. The developing solvent was PE:EA=20:1 to obtain 82 mg of 2-(3-methyl-1-methylenebutyl)aniline with a yield of 47%.

[0018] Example 3: o-Iodoaniline (1 mmol, 219 mg), palladium acetate (0.06 mmol, 13 mg) and n-butyldi(1-adamantyl)phosphine (0.264 mmol, 94 mg) were added to a 15 ml pressure bottle, protected with nitrogen, sealed, and then injected with a syringe. A mixed solution of N,N-diisopropylethylamine (2 mmol, 258 mg), 2 ml of acetonitrile and 4-methyl-1-pentene (5 mmol, 420 mg) was added. The stopcock was tightened, the temperature was raised to 85 °C and the reaction was carried out for 16 h. Thin layer chromatography was used for separation, and the developing solvent was PE:EA=20:1 to obtain 124 mg of 2-(3-methyl-1-methylenebutyl)aniline with a yield of 71%.

[0019] Example 4: o-Iodoaniline (1 mmol, 219 mg), bis(dibenzylideneacetonepalladium) (0.05 mmol, 28 mg) and n-butyldi(1-adamantyl)phosphine (0.264 mmol, 94 mg) were added to a 15 ml pressure bottle. The bottle was sealed under nitrogen protection. Then, a mixed solution of N,N-diisopropylethylamine (2 mmol, 258 mg), 2 ml of acetonitrile and 4-methyl-1-pentene (5 mmol, 420 mg) was injected with a syringe. The stopper was tightened, the temperature was raised to 85 °C and the reaction was carried out for 16 h. Thin layer chromatography was used for separation, and the developing solvent was PE:EA=20:1 to obtain 145 mg of 2-(3-methyl-1-methylenebutyl)aniline with a yield of 83%.

[0020] Example 5: Add o-iodoaniline (1 mmol, 219 mg), bis(dibenzylideneacetonepalladium) (0.05 mmol, 28 mg) and diphenylcyclohexylphosphine (0.264 mmol, 70 mg) into a 15 ml pressure bottle, protect with nitrogen, seal the bottle, and then inject a mixed solution of N,N-diisopropylethylamine (2 mmol, 258 mg), 2 ml acetonitrile and 4-methyl-1-pentene (5 mmol, 420 mg) with a syringe. Tighten the stopper, heat to 85 °C and react for 16 h. Separate by thin layer chromatography with developing solvent PE:EA=20:1 to obtain 68 mg of 2-(3-methyl-1-methylenebutyl)aniline with a yield of 39%.

[0021] Example 6: o-iodoaniline (1 mmol, 219 mg), bis(dibenzylideneacetonepalladium) (0.025 mmol, 14 mg) and n-butyldi(1-adamantyl)phosphine (0.125 mmol, 47 mg) were added to a 15 ml pressure bottle. The bottle was protected with nitrogen and sealed. Then, a mixed solution of N,N-diisopropylethylamine (2 mmol, 258 mg), 2 ml of acetonitrile and 4-methyl-1-pentene (5 mmol, 420 mg) was injected with a syringe. The bottle stopper was tightened, the temperature was raised to 85 °C and the reaction was carried out for 16 h. Thin layer chromatography was used for separation, and the developing solvent was PE:EA=20:1 to obtain 139 mg of 2-(3-methyl-1-methylenebutyl)aniline with a yield of 80%.

[0022] Example 7: o-Iodoaniline (1 mmol, 219 mg), bis(dibenzylideneacetonepalladium) (0.025 mmol, 14 mg) and n-butyldi(1-adamantyl)phosphine (0.075 mmol, 28 mg) were added to a 15 ml pressure bottle. The bottle was protected with nitrogen and sealed. Then, a mixed solution of N,N-diisopropylethylamine (2 mmol, 260 mg), 2 ml of acetonitrile and 4-methyl-1-pentene (5 mmol, 420 mg) was injected with a syringe. The bottle stopper was tightened, the temperature was raised to 85 °C and the reaction was carried out for 16 h. Thin layer chromatography was used for separation, and the developing solvent was PE:EA=20:1 to obtain 75 mg of 2-(3-methyl-1-methylenebutyl)aniline with a yield of 43%.

[0023] Example 8: o-Iodoaniline (1 mmol, 219 mg), bis(dibenzylideneacetonepalladium) (0.025 mmol, 14 mg) and n-butyldi(1-adamantyl)phosphine (0.125 mmol, 47 mg) were added to a 15 ml pressure bottle. The bottle was sealed under nitrogen protection. Then, a mixed solution of triethylamine (2 mmol, 202 mg), 2 ml of acetonitrile and 4-methyl-1-pentene (5 mmol, 420 mg) was injected with a syringe. The bottle stopper was tightened, the temperature was raised to 85 °C and the reaction was carried out for 16 h. Thin layer chromatography was used for separation, and the developing solvent was PE:EA=20:1 to obtain 129 mg of 2-(3-methyl-1-methylenebutyl)aniline with a yield of 74%.

[0024] Example 9: Add o-iodoaniline (1 mmol, 219 mg), bis(dibenzylideneacetonepalladium) (0.025 mmol, 14 mg) and n-butyldi(1-adamantyl)phosphine (0.125 mmol, 47 mg) into a 15 ml pressure bottle, protect with nitrogen, seal the bottle, and then inject a mixed solution of N,N-diisopropylethylamine (2 mmol, 260 mg), 2 ml of dimethyl sulfoxide and 4-methyl-1-pentene (5 mmol, 420 mg) with a syringe. Tighten the stopper, heat to 85 °C and react for 16 h. Separate by thin layer chromatography with developing solvent PE:EA=20:1 to obtain 115 mg of 2-(3-methyl-1-methylenebutyl)aniline with a yield of 66%.

[0025] Example 10: Add o-iodoaniline (1 mmol, 219 mg), bis(dibenzylideneacetonepalladium) (0.025 mmol, 14 mg) and n-butyldi(1-adamantyl)phosphine (0.125 mmol, 47 mg) into a 15 ml pressure bottle, protect with nitrogen, seal the bottle, and then inject a mixed solution of N,N-diisopropylethylamine (2 mmol, 260 mg), 2 ml acetonitrile and 4-methyl-1-pentene (3 mmol, 252 mg) with a syringe. Tighten the stopper, heat to 85 °C and react for 16 h. Separate by thin layer chromatography with developing solvent PE:EA=20:1 to obtain 122 mg of 2-(3-methyl-1-methylenebutyl)aniline with a yield of 70%.

[0026] Example 11: Add o-iodoaniline (1 mmol, 219 mg), bis(dibenzylideneacetonepalladium) (0.025 mmol, 14 mg) and n-butyldi(1-adamantyl)phosphine (0.125 mmol, 47 mg) into a 15 ml pressure bottle. Protect with nitrogen, seal the bottle, and then inject a mixed solution of N,N-diisopropylethylamine (2 mmol, 260 mg), 2 ml acetonitrile and 4-methyl-1-pentene (5 mmol, 420 mg) with a syringe. Tighten the stopper, heat to 95 °C for 16 h, separate by thin layer chromatography, use the developing solvent PE:EA=20:1, and obtain 143 mg of 2-(3-methyl-1-methylenebutyl)aniline with a yield of 82%.

Claims

1. A method for preparing 2-(3-methyl-1-methylenebutyl)aniline, characterized in that: Under the action of palladium phosphine composite catalyst, organic base and organic solvent, o-iodoaniline reacts with 4-methyl-1-pentene to generate 2-(3-methyl-1-methylenebutyl)aniline.

2. The method for preparing 2-(3-methyl-1-methylenebutyl)aniline according to claim 1, characterized in that: The palladium phosphine composite catalyst is composed of bis(dibenzylideneacetone palladium) or palladium acetate coordinated with a trivalent phosphine compound, wherein the trivalent phosphine compound is triisopropylphosphine fluoroborate, tricyclohexylphosphine fluoroborate, tri-tert-butylphosphine fluoroborate, biscyclohexylbiphenylphosphine borate, di-tert-butylmethylphosphine fluoroborate, biscyclohexylphenylphosphine, tricyclohexylphosphine, diphenylcyclohexylphosphine, tributylphosphine, n-butyldi(1-adamantyl)phosphine, di-n-butyl(1-adamantyl)phosphine, tri(p-tolyl)phosphine, triphenylphosphine, tri(pentafluorophenyl)phosphine, tri(tetramethoxyphenyl)phosphine, tri(4-bromophenyl)phosphine or tri(3.5-bis(trifluoromethyl)phenyl)phosphine, preferably biscyclohexylbiphenylphosphine borate or n-butyldi(1-adamantyl)phosphine, and the molar ratio of bis(dibenzylideneacetone palladium) or palladium acetate to the trivalent phosphine compound is 1:2-6, preferably 1:

5.

3. The method for preparing 2-(3-methyl-1-methylenebutyl)aniline according to claim 1, characterized in that: The organic base is N,N-diisopropylethylamine, diethylamine or triethylamine.

4. The method for preparing 2-(3-methyl-1-methylenebutyl)aniline according to claim 1, characterized in that: The reaction is carried out in an organic solvent, which is N,N-dimethylformamide, N,N-dimethylacetamide, toluene, tetrahydrofuran, dimethyl sulfoxide, 2-methyltetrahydrofuran, N-methylpyrrolidone or acetonitrile, preferably acetonitrile or dimethyl sulfoxide.

5. The method for preparing 2-(3-methyl-1-methylenebutyl)aniline according to claim 1, characterized in that: The molar ratio of o-iodoaniline to the palladium phosphine composite catalyst is 1:0.01-0.06, preferably 1:0.

025.

6. The method for preparing 2-(3-methyl-1-methylenebutyl)aniline according to claim 1, characterized in that: The molar ratio of o-iodoaniline to 4-methyl-1-pentene is 1:1-6, preferably 1:

5.

7. The method for preparing 2-(3-methyl-1-methylenebutyl)aniline according to claim 1, characterized in that: The molar ratio of o-iodoaniline to the organic base is 1:2-4, preferably 1:

2.

8. The method for preparing 2-(3-methyl-1-methylenebutyl)aniline according to claim 1, characterized in that: The reaction temperature is 60-110°C, preferably 85°C.

Images