Aniline synthesis method based on acetylenic ketone and allylamine

Abstract

The invention discloses an aniline synthesis method based on acetylenic ketone and allylamine, which comprises the following steps: by taking acetylenic ketone and allylamine as reactants, adding the acetylenic ketone and allylamine and a polar organic solvent into a reaction bottle, mixing, sealing the reaction bottle, and carrying out stirring reaction for 12-24 hours at 80-160 DEG C under anhydrous and anaerobic conditions; and separating and purifying to obtain a corresponding aniline product. The method has the characteristics of simple and easily available substrates, mild reaction conditions, wide substituent compatibility and the like, can efficiently and conveniently synthesize the polysubstituted aniline, enlarges the preparation scale, has good industrial practicability, and has extremely high application value in the fields of drug synthesis and the like.

Description

Technical Field

[0001] The invention belongs to the technical field of synthesis of small molecule organic compounds, and particularly relates to a method for synthesizing aniline based on alkynone and allylamine. Background Art

[0002] Aniline is an important class of organic compounds, which is widely used in various fields such as material chemistry, organic dye industry, pharmaceutical chemistry and synthetic chemistry. At the same time, in the field of organic synthesis, aniline, as an important platform molecule and synthetic building block, can be converted into various high-value organic compounds.

[0003] In industry, simple substituted anilines can be prepared by nitration-reduction of aromatic hydrocarbons. Relatively complex polysubstituted anilines can be synthesized by using amines and corresponding aromatic coupling precursors (such as aromatic halides, aromatic borides, etc.) through methods such as Buchwald-Hartwig coupling, Ullmann coupling, and Chan-Lam coupling. However, complex polysubstituted aromatic coupling precursors usually require multiple steps to prepare, so it is still challenging to use efficient and convenient methods to synthesize polysubstituted anilines in one step. Summary of the invention

[0004] The purpose of the present invention is to overcome the shortcomings of the prior art and provide a method for synthesizing aniline based on acetyl ketone and allylamine, thereby solving the problem of complex synthesis of polysubstituted aniline in the above-mentioned background technology.

[0005] The technical solution adopted by the present invention to solve the technical problem is as follows: a method for synthesizing aniline based on alkynone and allylamine is provided, alkynone and allylamine are used as reactants (with a 1.5:1-1:1.5 equal ratio), the two reactants and a polar organic solvent are added into a reaction bottle, mixed, and the reaction bottle is sealed, and the reaction is stirred at 80-160°C for 12-24 hours under anhydrous and oxygen-free conditions; after separation and purification, the corresponding aniline product is obtained.

[0006] In the present invention, an acid catalyst is also added to the reaction bottle, and the acid catalyst includes FeCl3, Sc(CF3SO3)3, MoO2Cl2, MoO2Cl2(dmf)2, BF3·H2O, and the amount of the acid catalyst is 0mol% to 20mol% of the mixed solution in the reaction bottle.

[0007] In the present invention, the chemical formula of the alkynone is The chemical formula of the allylamine The corresponding chemical formula of the aniline product is

[0008] Among them, the substituent R 1 H; R 2is H, alkyl, alkoxy, amino, aryl, acyl, aryl, substituted aryl, heterocycle, etc.; R 3 is H, halogen, alkyl, amino, ester, acyl, or an unsaturated group containing an olefinic group, aryl, substituted aryl, heterocycle, etc.; R 4 is an alkyl group or an unsaturated group containing an alkenyl group, an aryl group, a substituted aryl group, a heterocycle, etc.; R 5 It is H, halogen, alkyl, amino, ester, acyl, or an unsaturated group containing an alkenyl group, aryl, substituted aryl, heterocycle, etc.

[0009] In the present invention, the polar organic solvent includes DMSO, DMF, and DMA.

[0010] In the present invention, the separation and purification step comprises: cooling the reaction product to room temperature, vacuum evaporating to remove the solvent and then column chromatography.

[0011] In the present invention, the reaction temperature is 120° C. and the reaction time is 12 h.

[0012] In the present invention, a stirring bar is placed in the reaction bottle.

[0013] The reaction scheme of the present invention is as follows:

[0014]

[0015] The reaction process may include: 1,4-addition to generate intermediate INT-1; cyclodehydration to generate intermediate INT-2; electrocyclization to generate intermediate INT-3; and acid-catalyzed ring-opening aromatization to generate aniline product.

[0016] Compared with the background technology, this technical solution has the following advantages:

[0017] 1. Compared with other aniline synthesis methods, the substrate of this preparation method is simple, cheap, and easily available, the conditions are mild, and the substituent compatibility is wide.

[0018] 2. This preparation method is easy to prepare high-value aniline products on a large scale and has good industrial applicability.

[0019] 3. This preparation method does not require the use of harmful heavy metals or expensive precious metal catalysts, and can more conveniently and safely prepare various aniline-based pharmaceutically active molecules. DETAILED DESCRIPTION

[0020] Example 1

[0021] This embodiment provides a method for synthesizing N-methyl-2-phenyl-4-(p-methylphenyl)aniline, and the reaction route is:

[0022]

[0023] The specific steps are as follows:

[0024] Acid catalyst MoO2Cl2(dmf)2 (6.9 mg, 0.02 mmol, 10 mol%), 1-(p-methylphenyl)-3-phenylprop-2-ynone 1a (44.1 mg, 0.2 mmol, 1.0 equiv), methylallylamine 2a (15.6 mg, 0.22 mmol, 1.1 equiv), and dry DMSO (1 mL) were added to a Young Schlenk tube under nitrogen. The reaction tube was sealed and stirred at 120°C. After 12 h, the reaction tube was cooled to room temperature, the DMSO solvent was removed by vacuum evaporation, and then column chromatography was performed to obtain the corresponding product N-methyl-2-phenyl-4-(p-methylphenyl)aniline 3a (yellow oil, 52.1 mg, yield 95%).

[0025] The characterization data of the compound are as follows 1 H NMR (400MHz, CDCl3): δ = 7.62 (dd, J = 8.4, 2.3Hz, 1H), 7.60–7.50 (m, 6H), 7.49–7.43 (m, 2 H),7.32–7.25(m,2H),6.85(d,J=8.4Hz,1H),4.11(brs,1H),2.92(s,3H),2.46(s,3H). 13 C NMR (100MHz, CDCl3): δ = 145.4, 139.4, 138.3, 135.6, 129.7, 129.4, 129.3, 128.9, 128.6, 127.8, 127.3, 127.1, 126.1, 110.1, 30.8, 21.0. IR (thinfilm): ν max (cm -1 )=3432,3022,2918,1610,1528,1505,1492,1306,1172,806,773,704.HRMS(ESI)calcd for C 20 H 20 N[M+H] + :274.1590.Found:274.1590.

[0026] Example 2

[0027] The difference between this example and Example 1 is that DMF is used as the solvent, and the yield of aniline 3a is 78%.

[0028] Example 3

[0029] The difference between this example and Example 1 is that the feeding amount of methylallylamine is 21.3 mg (0.3 mmol, 1.5 equiv), and the added acid catalyst is FeCl3 (3.2 mg, 0.02 mmol, 10 mol%), and the yield of aniline 3a is 87%.

[0030] Example 4

[0031] The difference between this example and Example 1 is that the amount of methylallylamine added is 21.3 mg (0.3 mmol, 1.5 equiv), and no acid catalyst is added (0 equiv), and the yield of aniline 3a is 73%.

[0032] Example 5

[0033] This embodiment provides a method for synthesizing N-methyl-2-adamantyl-4-cyclohexyl-6-methylaniline, and the reaction route is:

[0034]

[0035] The specific steps are as follows:

[0036] Acid catalyst MoO2Cl2(dmf)2 (6.9 mg, 0.02 mmol, 10 mol%), 1-(adamantyl)-3-cyclohexyl-2-ynone 1b (81.1 mg, 0.3 mmol, 1.5 equiv), N-methyl-(2'-methyl)allylamine 2b (21.1 mg, 0.2 mmol, 1.0 equiv), and dry DMSO (1 mL) were added to a Young Schlenk tube under nitrogen. The reaction tube was sealed and stirred at 140°C. After 12 h, the reaction tube was cooled to room temperature, the DMSO solvent was removed by vacuum evaporation, and then column chromatography was performed to obtain the corresponding product N-methyl-2-adamantyl-4-cyclohexyl-6-methylaniline 3b (yellow oil, 31.0 mg, yield 46%).

[0037] The characterization data of the compound are as follows 1 H NMR (400MHz, CDCl3): δ = 7.08 (d, J = 2.3Hz, 1H), 7.00 (d, J = 1.9Hz, 1H), 2.86–2.80 (m, 1H), 2.75 (s, 3H), 2.34 (s, 3H), 2.11–2.07(m,3H),1.93–1.90(m,6H),1.88–1.80(m,5H),1.80–1.76(m,6H),1.75–1.71(m,1H),1.53–1.42(m,4H). 13CNMR (100MHz, CDCl3): δ = 145.6, 143.3, 139.7, 129.9, 124.9, 121.0, 43.3, 38.7, 37.0, 36.9, 35.7, 34.7, 29.1, 27.2, 26.3, 18.8. IR (thin film): ν max (cm -1 )=3381,2906,2849,2658,1719,1687,1601,1482,1449,1316,1142,978,867,739.HRMS(ESI)calcd for C 24 H 36 N[M+H] + :338.2842.Found:338.2843

[0038] Example 6

[0039] This embodiment provides a method for synthesizing N-methyl-2-(3'-thienyl)-4-(1"-toluenesulfonyl-5"-indolyl)aniline, and the reaction route is:

[0040]

[0041] The specific steps are as follows:

[0042] Acid catalyst MoO2Cl2(dmf)2 (6.9 mg, 0.02 mmol, 10 mol%), 1-(1'-toluenesulfonyl-5'-indolyl)-3-(3"-thienyl)prop-2-ynone 1c (0.2 mmol, 1.0 equiv), methylallylamine 2a (0.22 mmol, 1.1 equiv), and dry DMSO (1 mL) were added to a Young Schlenk tube under nitrogen. The reaction tube was sealed and stirred at 120°C. After 12 h, the reaction tube was cooled to room temperature, the DMSO solvent was removed by vacuum evaporation, and then column chromatography was performed to obtain the corresponding product N-methyl-2-(3'-thienyl)-4-(1"-toluenesulfonyl-5"-indolyl)aniline 3c (yellow oil, 84.7 mg, yield 92%).

[0043] The characterization data of the compound are as follows 1H NMR (400MHz, CDCl3): δ=8.09–8.04(m,1H),7.83–7.79(m,2H),7.72(d,J=1.4Hz,1H),7.59(d,J=3.7Hz,1H),7.58–7.52(m,3H),7.39(dd,J=5.2, 1.1Hz,1H),7.23(dd,J=3.5,1.1Hz,1H),7.22–7.18(m,2H),7.16(dd,J=5.1,3.5Hz,1H),6.81–6.76(m,1H),6.69(dd,J=3.6,0.6Hz,1H),4.48(br s,1H),2.88(s,3H),2.31(s,3H). 13 C NMR (100MHz, CDCl3): δ=145.9,144.8,140.6,136.5,135.2,133.6,131.3,129.7,129.6,129.4,1 28.1,127.5,126.6,126.1,125.4,123.5,119.8,118.6,113.6,110.3,109.2,30.6,21.4.IR(thin film):ν max (cm -1 )=3424,2923,1731,1608,1515,1456,1371,1272,1131,810,703,671,588,538.HRMS(ESI)calcd for C 26 H 23 N2O2S2[M+H] + :459.1195.Found:459.1190.

[0044] The above embodiments are only used to illustrate the technical solutions of the present invention, rather than to limit it. Although the present invention has been described in detail with reference to the aforementioned embodiments, those skilled in the art should understand that the technical solutions described in the aforementioned embodiments may still be modified, or some or all of the technical features thereof may be replaced by equivalents. However, these modifications or replacements do not deviate the essence of the corresponding technical solutions from the scope of the technical solutions of the embodiments of the present invention.

Claims

1. A method for synthesizing aniline based on alkynone and allylamine, characterized in that: Using alkynone and allylamine as reactants, polar organic solvents of the two are added into a reaction bottle and mixed, and the reaction bottle is sealed, and stirred to react at 80-160° C. for 12-24 hours under anhydrous and oxygen-free conditions; after separation and purification, the corresponding aniline product is obtained.

2. A method for synthesizing aniline based on alkynone and allylamine according to claim 1, characterized in that: The chemical structural formula of the alkynone is The chemical structural formula of the allylamine is The corresponding chemical structure of the aniline product is Among them, R 1 For H, R 2 is H, alkyl, alkoxy, amino, aryl, acyl, aryl, substituted aryl, heterocycle, 3 , R 5 is H, halogen, alkyl, amino, ester, acyl, or an unsaturated group containing an olefinic group, aryl, substituted aryl, or heterocycle, R 4 It is an alkyl group or an unsaturated group containing an alkenyl group, an aryl group, a substituted aryl group, or a heterocycle.

3. The method for synthesizing aniline based on alkynone and allylamine according to claim 1, characterized in that: The alkynone and allylamine are fed in an equiv of 1.5:1 to 1:1.

5.

4. The method for synthesizing aniline based on alkynone and allylamine according to claim 1, characterized in that: An acid catalyst is also added into the reaction bottle.

5. A method for synthesizing aniline based on alkynone and allylamine according to claim 4, characterized in that: The acid catalyst includes FeCl3, MoO2Cl2, MoO2Cl2(dmf)2, and BF3·H2O.

6. The method for synthesizing aniline based on alkynone and allylamine according to claim 5, characterized in that: The amount of the acid catalyst added to the reaction flask is 0 mol% to 20 mol% of the mixed solution.

7. The method for synthesizing aniline based on alkynone and allylamine according to claim 1, characterized in that: The polar organic solvent includes DMSO, DMF, and DMA.

8. The method for synthesizing aniline based on alkynone and allylamine according to claim 1, characterized in that: The separation and purification step comprises: cooling the reaction product to room temperature, vacuum evaporating to remove the solvent, and then column chromatography.

9. The method for synthesizing aniline based on alkynone and allylamine according to claim 1, characterized in that: The reaction temperature was 120°C.

10. The method for synthesizing aniline based on alkynone and allylamine according to claim 1, characterized in that: The reaction time is 12h.

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