CN112441981A - 1,2, 5-polysubstituted imidazole derivative and synthesis method and application thereof - Google Patents
1,2, 5-polysubstituted imidazole derivative and synthesis method and application thereof Download PDFInfo
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- C07D233/64—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
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Abstract
The invention relates to the technical field of synthetic medicine and chemical industry, in particular to a 1,2, 5-polysubstituted imidazole derivative and a synthetic method and application thereof. A1, 2, 5-polysubstituted imidazole derivative has a structure shown in the formula
Description
Technical Field
The invention belongs to the field of synthetic medicine and chemical engineering, and particularly relates to a 1,2, 5-polysubstituted imidazole derivative, and a synthetic method and application thereof.
Background
The imidazole organic matters are used as an important pharmacophore, have wide application in pharmaceutical chemistry and pesticide chemistry, and particularly play an important role in the aspects of resisting fungi and mildew and treating trichomoniasis. The 1,2, 5-polysubstituted imidazole has outstanding medicinal activity, and for example, metronidazole and tinidazole which are commonly used for treating oral anaerobe are 1,2, 5-polysubstituted imidazole medicines. Therefore, as an important pharmacophore, the 1,2, 5-polysubstituted imidazole has great application potential in drug development. Thus, the synthesis of 1,2, 5-polysubstituted imidazole structures has always been a focus of research by workers in organic synthesis and drug synthesis.
At present, although the synthesis method of the related 1,2, 5-polysubstituted imidazole structure has been reported, the method has the defects of difficult obtainment of raw materials, insufficient use range of substrates, complicated operation, poor regioselectivity and the like.
Disclosure of Invention
Aiming at the defects of the prior art, the invention overcomes the defects in the synthesis method of the prior art, and provides the synthesis method for synthesizing the 1,2, 5-polysubstituted imidazole compound in one step, and the method has the advantages of cheap and easily obtained raw materials, wide substrate universality, low catalyst consumption, simple and safe operation, high regioselectivity and the like.
The invention enables the synthesis of the 1,2, 5-polysubstituted imidazole compound to be simpler and more feasible, and powerfully promotes the construction of the 1,2, 5-polysubstituted imidazole compound library.
The technical scheme adopted by the invention is as follows:
the invention provides a 1,2, 5-polysubstituted imidazole derivative, the structure of which is shown as the following formula (1):
wherein R is1Is phenyl, C1-C10Alkyl-substituted phenyl, halogen-substituted phenyl, C1-C10Alkoxy-substituted phenyl, naphthyl, furyl, thienyl; r2Is phenyl, C1-C10Alkyl-substituted phenyl, halogen-substituted phenyl, C1-C10Alkoxy-substituted phenyl, naphthyl, pyrrolyl, furanyl, thienyl; r3Is phenyl, C1-C10Alkyl-substituted phenyl, halogen-substituted phenyl, C1-C10Alkoxy substituted phenyl, naphthyl, thienyl.
Preferably, said R is1Is phenyl, p-methylphenyl, p-chlorophenyl, p-bromophenyl, p-methoxyphenyl, 3, 5-dichlorophenyl, 3, 5-dimethylphenyl, m-bromophenyl, m-methoxyphenyl, o-methylAny one group of oxyphenyl, o-benzyloxyphenyl, o-fluorophenyl, 2-naphthyl, 2-pyrrolyl, 2-furyl and 2-thienyl;
R2is any one of p-methylphenyl, p-chlorophenyl, p-bromophenyl, p-methoxyphenyl, 3, 5-dichlorophenyl, 3, 5-dimethylphenyl, m-bromophenyl, m-methoxyphenyl, o-benzyloxyphenyl, o-fluorophenyl, 2-naphthyl, 2-pyrrolyl, 2-furyl and 2-thienyl;
R3is any one of p-methylphenyl, p-chlorophenyl, p-bromophenyl, p-methoxyphenyl, 2-naphthyl and 2-thienyl.
The invention also provides a synthesis method of the 1,2, 5-polysubstituted imidazole derivative shown as the formula (1), which comprises the following steps of taking styryl azide, aromatic aldehyde and aromatic amine as raw materials, taking rhodium acetate and phosphoric acid as catalysts and taking an organic solvent as a solvent, and carrying out one-step reaction to obtain the 1,2, 5-polysubstituted imidazole derivative:
the synthesis reaction process is shown in a reaction formula (I):
the method specifically comprises the following steps: placing the styryl azide, the aromatic aldehyde, the aromatic amine, the rhodium acetate and the phosphoric acid into a reaction bottle, adding an organic solvent to form a mixed solution, and heating to react to obtain the 1,2, 5-polysubstituted imidazole derivative.
The molar ratio of the raw materials is styryl azide: aromatic aldehyde: aromatic amine: rhodium acetate: phosphoric acid = (2.0-3.0): (1.0-1.5): (1.0-1.5): (0.02-0.05): (0.1-0.2); the reaction temperature is 90-110 ℃; the reaction time is 12-18 h; the organic solvent comprises 1, 2-dichloroethane, aromatic hydrocarbon; wherein the aromatic hydrocarbon is selected from any one or more of toluene, chlorobenzene, xylene, fluorobenzene and anisole. Preferably, the reaction temperature is 100 ℃; the reaction time is 12 h; the organic solvent is toluene and 1, 2-dichloroethane.
The invention has the beneficial effects that:
1. the 1,2, 5-polysubstituted imidazole derivative and the synthesis method thereof have the advantages of cheap and easily obtained raw materials, simple and safe operation, and can synthesize the 1,2, 5-polysubstituted imidazole heterocyclic compound in one step, thereby overcoming the defects of the synthesis method of the compound. Has the advantages of wide substrate universality, low catalyst consumption, high regioselectivity and the like.
2. The 1,2, 5-polysubstituted imidazole derivative and the synthesis method thereof have higher yield. Taking styryl azide, aromatic aldehyde and aromatic amine as raw materials, taking rhodium acetate and phosphoric acid as catalysts, taking an organic solvent as a solvent, and carrying out one-step reaction at 90-110 ℃ to obtain the 1,2, 5-polysubstituted imidazole derivative. Has the advantages of high atom economy and the like.
3. The 1,2, 5-polysubstituted imidazole derivative and the synthesis method thereof realize the multicomponent reaction of styryl azide, aromatic aldehyde and aromatic amine for the first time, and construct the 1,2, 5-polysubstituted imidazole derivative with good biological activity in one step. The imidazole derivatives obtained by synthesis widely exist in drug molecules on the market and are important organic synthesis and medical intermediates.
4. The 1,2, 5-polysubstituted imidazole derivative and the synthesis method thereof have extremely low dosage of the required catalyst. Wherein, when the dosage of rhodium acetate is only 2% of the substrate material and the dosage of phosphoric acid is only 10% of the substrate material, the polysubstituted imidazole derivative can be obtained with moderate to good yield, and the high efficiency and the practicability of the reaction are reflected.
Drawings
FIGS. 1A-1B are nuclear magnetic resonance diagrams of 1,2, 5-polysubstituted imidazole derivatives according to example 8 of the present invention1H NMR (FIG. 1A),13A C NMR (FIG. 1B) spectrum;
FIGS. 2A-2B show NMR spectra of 1,2, 5-polysubstituted imidazole derivatives of example 9 of the invention1H NMR (FIG. 2A),13A C NMR (FIG. 2B) spectrum;
FIGS. 3A to 3B show examples 10 of the present invention which are 1,2Nuclear magnetic resonance of 5-polysubstituted imidazole derivatives1H NMR (FIG. 3A),13A C NMR (FIG. 3B) spectrum;
FIGS. 4A-4B are NMR's of 1,2, 5-polysubstituted imidazole derivatives of example 11 of the invention1H NMR (FIG. 4A),13A C NMR (FIG. 4B) spectrum;
FIGS. 5A-5B show NMR's of 1,2, 5-polysubstituted imidazole derivatives of example 12 of the invention1H NMR (FIG. 5A),13A C NMR (FIG. 5B) spectrum;
FIGS. 6A-6B show NMR spectra of 1,2, 5-polysubstituted imidazole derivatives of example 13 of the invention1H NMR (FIG. 6A),13A C NMR (FIG. 6B) spectrum;
FIGS. 7A-7B show NMR spectra of 1,2, 5-polysubstituted imidazole derivatives of example 14 of the invention1H NMR (FIG. 7A),13C NMR (FIG. 7B) spectrum.
Detailed Description
The technical solution of the present invention is further described in detail below by using specific embodiments and with reference to the accompanying drawings. The present invention is not limited to the following embodiments, and variations and advantages that can be conceived by a person skilled in the art are to be included in the scope of the claims of the present invention without departing from the spirit and scope of the inventive concept.
Example 1
The 1,2, 5-polysubstituted imidazole derivative has a structure shown in a formula (1):
wherein R is1Is phenyl, C1-C10Alkyl-substituted phenyl, halogen-substituted phenyl, C1-C10Alkoxy-substituted phenyl, naphthyl, furyl, thienyl; r2Is phenyl, C1-C10Alkyl-substituted phenyl, halogen-substituted phenyl, C1-C10Alkoxy-substituted phenyl,Naphthyl, pyrrolyl, furanyl, thienyl; r3Is phenyl, C1-C10Alkyl-substituted phenyl, halogen-substituted phenyl, C1-C10Alkoxy substituted phenyl, naphthyl, thienyl.
Preferably, said R is1Is p-methylphenyl, p-chlorophenyl, p-bromophenyl, p-methoxyphenyl, 3, 5-dichlorophenyl, 3, 5-dimethylphenyl, m-bromophenyl, m-methoxyphenyl, o-benzyloxyphenyl, o-fluorophenyl, 2-naphthyl, 2-pyrrolyl, 2-furyl or 2-thienyl; r2Is p-methylphenyl, p-chlorophenyl, p-bromophenyl, p-methoxyphenyl, 3, 5-dichlorophenyl, 3, 5-dimethylphenyl, m-bromophenyl, m-methoxyphenyl, o-benzyloxyphenyl, o-fluorophenyl, 2-naphthyl, 2-pyrrolyl, 2-furyl or 2-thienyl; r3Is p-methylphenyl, p-chlorophenyl, p-bromophenyl, p-methoxyphenyl, 2-naphthyl, 2-thienyl.
Example 2
The invention relates to a synthesis method of 1,2, 5-polysubstituted imidazole derivatives, which comprises the steps of taking styryl azide, aromatic aldehyde and aromatic amine as raw materials, taking rhodium acetate and phosphoric acid as catalysts, taking an organic solvent as a solvent, and carrying out one-step reaction to obtain the 1,2, 5-polysubstituted imidazole derivatives; the reaction process is shown as a reaction formula (I):
placing the styryl azide, the aromatic aldehyde, the aromatic amine, the rhodium acetate and the phosphoric acid into a reaction bottle, adding an organic solvent to form a mixed solution, and heating to react to obtain the 1,2, 5-polysubstituted imidazole derivative.
The molar ratio of the raw materials is styryl azide: aromatic aldehyde: aromatic amine: rhodium acetate: phosphoric acid = (2.0-3.0): (1.0-1.5): (1.0-1.5): (0.02-0.05): (0.1-0.2).
The organic solvent adopts 1, 2-dichloroethane or aromatic hydrocarbon; wherein the aromatic hydrocarbon is selected from any one or more of toluene, chlorobenzene, xylene, fluorobenzene and anisole.
The process of obtaining the 1,2, 5-polysubstituted imidazole derivative through reaction further comprises the steps of separation and purification; the separation and purification is to perform column chromatography by using a mixed solution of ethyl acetate and petroleum ether in a volume ratio of 1 (20-5).
The 1,2, 5-polysubstituted imidazole derivatives prepared by the synthesis method have wide application in pesticide chemistry, pharmaceutical chemistry and organic synthesis.
Example 3:
the method for synthesizing the 1,2, 5-polysubstituted imidazole derivative in the embodiment is different from the embodiment 2 in that the molar ratio of the raw materials is styryl azide compound: aromatic aldehyde: aromatic amine: rhodium acetate: phosphoric acid =2.0:1.0:1.0:0.02: 0.1.
Example 4:
the method for synthesizing the 1,2, 5-polysubstituted imidazole derivative in the embodiment is different from the embodiment 2 in that the molar ratio of the raw materials is styryl azide compound: aromatic aldehyde: aromatic amine: rhodium acetate: phosphoric acid =2.0:1.0:1.0:0.05: 0.2.
Example 5:
the method for synthesizing the 1,2, 5-polysubstituted imidazole derivative in the embodiment is different from the embodiment 2 in that the molar ratio of the raw materials is styryl azide compound: aromatic aldehyde: aromatic amine: rhodium acetate: phosphoric acid =3.0:1.5:1.5:0.02: 0.1.
Example 6:
the method for synthesizing the 1,2, 5-polysubstituted imidazole derivative in the embodiment is different from the embodiment 2 in that the molar ratio of the raw materials is styryl azide compound: aromatic aldehyde: aromatic amine: rhodium acetate: phosphoric acid =3.0:1.5:1.5:0.05: 0.2.
Example 7:
the method for synthesizing the 1,2, 5-polysubstituted imidazole derivative in the embodiment is different from the embodiment 2 in that the molar ratio of the raw materials is styryl azide compound: aromatic aldehyde: aromatic amine: rhodium acetate: phosphoric acid =2.5:1.2:1.2:0.03: 0.15.
Example 8:
styryl azide (0.3 mmol), aniline (0.15 mmol), benzaldehyde (0.15 mmol), rhodium acetate (0.002 mmol) and phosphoric acid (0.01 mmol) are added with 2.5mL of toluene, stirred in a 100 ℃ oil bath for 12h, and the solvent is removed under reduced pressure to obtain a crude product, the structural formula of which is shown as (4-1). And (3) carrying out column chromatography on the crude product (ethyl acetate: petroleum ether = 1: 20-1: 10) to obtain a pure product. The yield was 80%. Nuclear magnetic resonance1H NMR、13C NMR spectra are shown in FIG. 1A and FIG. 1B,1H NMR (500 MHz, CDCl3): δ 7.43-7.30 (m, 6H), 7.26-7.19 (m, 6H), 7.14-7.04 (m, 4H) ppm; 13C NMR (125 MHz, CDCl3): δ 148.1, 137.3, 135.1, 130.7, 129.9, 129.4, 128.8, 128.5, 128.5, 128.3, 128.2, 128.2, 128.1, 127.3 ppm。
example 9:
styryl azide (0.3 mmol), p-methylaniline (0.15 mmol), p-bromobenzaldehyde (0.15 mmol), rhodium acetate (0.002 mmol) and phosphoric acid (0.01 mmol) were added to 2.5mL of toluene, stirred in a 100 ℃ oil bath for 12h, and the solvent was removed under reduced pressure to give a crude product of which the formula is shown in (4-2). And (3) carrying out column chromatography on the crude product (ethyl acetate: petroleum ether = 1: 20-1: 10) to obtain a pure product. The yield was 75%. Nuclear magnetic resonance1H NMR、13C NMR spectra are shown in FIG. 2A and FIG. 2B,1H NMR (500 MHz, CDCl3): δ 7.37-7.33 (m, 3H), 7.21 (d, J = 6.9 Hz, 5H), 7.14 (d, J = 7.6 Hz, 2H), 7.08 (s, 2H), 6.97 (d, J = 7.5 Hz, 2H), 2.38 (s, 3H) ppm; 13C NMR (125 MHz, CDCl3): δ 147.0, 138.8, 135.5, 134.3, 131.3, 130.2, 130.2, 129.7, 129.7, 128.5, 128.3, 127.9, 127.4, 127.0, 122.5, 21.3 ppm.
example 10:
2.5mL of toluene was added to styryl azide (0.3 mmol), aniline (0.15 mmol), p-methoxybenzaldehyde (0.15 mmol), rhodium acetate (0.002 mmol) and phosphoric acid (0.01 mmol), and the mixture was stirred in a 100 ℃ oil bath for 12 hours, and the solvent was removed under reduced pressure to obtain a crude product having the formula shown in (4-3). And (3) carrying out column chromatography on the crude product (ethyl acetate: petroleum ether = 1: 10-1: 5) to obtain a pure product. The yield was 82%. Nuclear magnetic resonance1H NMR、13C NMR spectra are shown in FIG. 3A and FIG. 3B,1H NMR (400 MHz, CDCl3): δ 7.37-7.29 (m, 4H), 7.24 (d, J = 3.6 Hz, 2H), 7.18 (dd, J = 6.3, 3.7 Hz, 3H), 7.07 (ddd, J = 9.6, 6.8, 1.8 Hz, 4H), 6.74 (d, J = 8.9 Hz, 2H), 3.75 (s, 3H) ppm; 13C NMR (100 MHz, CDCl3): δ 159.6, 148.0, 137.3, 134.7, 130.2, 129.9, 129.4, 128.5, 128.5, 128.4, 128.3, 127.8, 127.3, 123.1, 113.6, 55.2 ppm。
example 11:
2.5mL of toluene was added to styryl azide (0.3 mmol), p-bromoaniline (0.15 mmol), p-tolualdehyde (0.15 mmol), rhodium acetate (0.002 mmol) and phosphoric acid (0.01 mmol), and the mixture was stirred in a 100 ℃ oil bath for 12 hours, and the solvent was removed under reduced pressure to obtain a crude product having the formula shown in (4-4). And (3) carrying out column chromatography on the crude product (ethyl acetate: petroleum ether = 1: 20-1: 10) to obtain a pure product. The yield was 76%. Nuclear magnetic resonance1H NMR、13C NMR spectra are shown in FIGS. 4A and 4B,1H NMR (400 MHz, CDCl3): δ 7.49-7.41 (m, 2H), 7.32 (s, 1H), 7.26-7.17 (m, 5H), 7.06 (dd, J = 6.5, 3.5 Hz, 4H), 6.98-6.92 (m, 2H), 2.32 (s, 3H) ppm; 13C NMR (100 MHz, CDCl3): δ 148.2, 138.4, 136.3, 134.7, 132.6, 129.8, 129.6, 129.0, 128.8, 128.6, 128.4, 128.3, 127.5, 127.5, 122.3, 21.3 ppm。
example 12:
2.5mL of toluene was added to styryl azide (0.3 mmol), p-bromoaniline (0.15 mmol), benzaldehyde (0.15 mmol), rhodium acetate (0.002 mmol) and phosphoric acid (0.01 mmol), and the mixture was stirred in a 100 ℃ oil bath for 12 hours, and the solvent was removed under reduced pressure to obtain a crude product having the formula shown in (4-5). And (3) carrying out column chromatography on the crude product (ethyl acetate: petroleum ether = 1: 20-1: 10) to obtain a pure product. The yield was 81%. Nuclear magnetic resonance1H NMR、13C NMR spectra are shown in FIG. 5A and FIG. 5B,1H NMR (400 MHz, CDCl3): δ 7.46-7.39 (m, 2H), 7.33-7.27 (m, 3H), 7.23 (td, J = 6.3, 3.2 Hz, 6H), 7.04 (dd, J = 6.6, 3.0 Hz, 2H), 6.96-6.89 (m, 2H) ppm; 13C NMR (100 MHz, CDCl3): δ 148.0, 136.2, 134.9, 132.7, 130.3, 129.8, 129.5, 128.9, 128.6, 128.5, 128.3, 127.6, 122.4 ppm。
example 13:
styryl azide (0.3 mmol), p-bromoaniline (0.15 mmol), 2-thiophenecarboxaldehyde (0.15 mmol), rhodium acetate (0.002 mmol) and phosphoric acid (0.01 mmol) are added with 2.5mL of toluene, stirred in a 100 ℃ oil bath for 12h, and the solvent is removed under reduced pressure to obtain a crude product, wherein the structural formula of the crude product is shown as (4-6). And (3) carrying out column chromatography on the crude product (ethyl acetate: petroleum ether = 1: 20-1: 10) to obtain a pure product. The yield was 84%. Nuclear magnetic resonance1H NMR、13C NMR spectra are shown in FIGS. 6A and 6B,1H NMR (500 MHz, CDCl3): δ 7.60-7.54 (m, 2H), 7.31 (s, 1H), 7.25-7.21 (m, 4H), 7.18-7.13 (m, 2H), 7.12-7.07 (m, 2H), 6.87 (dd, J = 5.0, 3.8 Hz, 1H), 6.60 (dd, J = 3.7, 0.9 Hz, 1H) ppm; 13C NMR (125 MHz, CDCl3): δ 143.5, 135.9, 135.2, 133.0, 133.0, 130.5, 129.2, 128.5, 128.4, 128.3, 127.7, 127.3, 126.6, 126.0, 123.5 ppm。
example 14:
styryl azide (0.3 mmol), p-anisidine (0.15 mmol), 2-benzyloxybenzaldehyde (0.15 mmol), rhodium acetate (0.002 mmol) and phosphoric acid (0.01 mmol) were added to 2.5mL of toluene, stirred in a 100 ℃ oil bath for 12 hours, and the solvent was removed under reduced pressure to give a crude product of the formula (4-7). And (3) carrying out column chromatography on the crude product (ethyl acetate: petroleum ether = 1: 20-1: 5) to obtain a pure product. The yield was 77%. Nuclear magnetic resonance1H NMR、13C NMR spectra are shown in FIG. 7A and FIG. 7B,1H NMR (500 MHz, CDCl3): δ 7.47 (dd, J = 7.5, 1.6 Hz, 1H), 7.38 (s, 1H), 7.25-7.17 (m, 7H), 7.10 (dd, J = 7.7, 1.6 Hz, 2H), 7.06 (d, J = 6.5 Hz, 2H), 6.96 (t, J = 7.5 Hz, 1H), 6.81-6.76 (m, 2H), 6.71 (d, J = 8.3 Hz, 1H), 6.63-6.56 (m, 2H), 4.79 (s, 2H), 3.71 (s, 3H) ppm; 13C NMR (125 MHz, CDCl3): δ 158.7, 156.7, 146.7, 137.0, 134.1, 132.4, 130.6, 130.2, 130.0, 128.6, 128.3, 128.3, 128.2, 127.7, 127.6, 127.1, 126.6, 121.2, 120.8, 113.7, 112.8, 70.1, 55.3 ppm。
example 15:
the experimental procedure of this example was substantially the same as in example 8, wherein the aromatic amine used in this example was p-chloroaniline and the aromatic aldehyde was p-tolualdehyde, and the obtained product was represented by the formula (4-8). The yield was 71%.
Example 16:
the experimental procedure of this example was substantially the same as in example 8, the aromatic amine used in this example was o-fluoroaniline and the aromatic aldehyde was p-methoxybenzaldehyde, and the obtained product was represented by the formula (4-9). The yield was 81%.
Example 17:
the experimental procedure of this example is substantially the same as example 8, the aromatic amine used in this example is 2-naphthylamine, the aromatic aldehyde is m-methoxybenzaldehyde, and the obtained product is represented by structural formula (4-10). The yield was 70%.
Example 18:
the experimental procedure of this example was substantially the same as in example 8, the aromatic amine used in this example was 3, 5-dimethylaniline and the aromatic aldehyde was 2-naphthaldehyde, and the resulting product was represented by the formula (4-11). The yield was 78%.
Example 19:
the experimental procedure of this example was substantially the same as in example 8, the aromatic amine used in this example was m-bromoaniline, the aromatic aldehyde was 2-furaldehyde, and the resulting product was represented by structural formula (4-12). The yield was 76%.
Example 20:
the experimental method of this example is substantially the same as example 8, the aromatic amine used in this example is 3, 5-dichloroaniline, the aromatic aldehyde is 2-thiophenecarboxaldehyde, the azide compound is p-methylstyrene azide, and the obtained product is represented by the structural formula (4-13). The yield was 69%.
Example 21:
the experimental procedure of this example is substantially the same as in example 8, the azide compound used in this example is p-chlorostyryl azide, and the resulting product is represented by the formula (4-14). The yield was 72%.
Example 22:
the experimental method of this example is substantially the same as example 8, the aromatic amine used in this example is m-methoxyaniline, the aromatic aldehyde is o-fluorobenzaldehyde, the azide compound is p-methoxystyryl azide, and the obtained product is represented by the structural formula (4-15). The yield was 68%.
Example 23:
the experimental procedure of this example is substantially the same as example 8, the aromatic amine used in this example is o-anisidine, the aromatic aldehyde is 2-pyrrolecarboxaldehyde, and the resulting product is represented by the structural formula (4-16). The yield was 75%.
Example 24:
the experimental method of this example is substantially the same as example 8, the aromatic amine used in this example is p-chloroaniline, the aromatic aldehyde is 2-thiophenecarboxaldehyde, and the azide compound is 2-naphthylvinyl azide, and the obtained product is represented by the structural formula (4-17). The yield was 65%.
Example 25:
this example was conducted in the same manner as in example 8 except that p-benzyloxyaniline was used as the aromatic amine and m-bromobenzaldehyde was used as the aromatic aldehyde, and the obtained product was represented by the following structural formulae (4-18). The yield was 72%.
Example 26:
the experimental method of this example is the same as example 8, the aromatic amine used in this example is 3, 5-dimethylaniline, the aromatic aldehyde is 3, 5-dichlorobenzaldehyde, and the obtained product is represented by structural formula (4-19). The yield was 78%.
Example 27:
the experimental method of this example is the same as example 8, the aromatic amine used in this example is p-methylaniline, the aromatic aldehyde is p-tolualdehyde, the azide compound is p-methylstyrene azide, and the obtained product is represented by the structural formula (4-20). The yield was 82%.
Example 28:
the experimental procedure of this example was the same as in example 1, the aromatic amine used in this example was o-benzyloxyaniline, the aromatic aldehyde was o-benzyloxybenzaldehyde, and the obtained product was represented by the structural formula (4-21). The yield was 75%.
The 1,2, 5-polysubstituted imidazole derivative and the synthesis method thereof can synthesize the 1,2, 5-polysubstituted imidazole heterocyclic compound in one step, and realize the multicomponent reaction of styryl azide, aromatic aldehyde and aromatic amine for the first time. The method constructs 1,2, 5-polysubstituted imidazole derivatives with good biological activity in one step, and the imidazole derivatives are important organic synthesis and medical intermediates. Cheap and easily available raw materials, wide substrate universality, low catalyst consumption, simple and safe operation, high regioselectivity and the like. The defects of the synthesis method of the compounds are overcome. Has the advantages of high atom economy, high yield and the like.
Claims (10)
1. A1, 2, 5-polysubstituted imidazole derivative has a structure shown in formula (1):
wherein R is1Or R2Is phenyl, C1-C10Alkyl-substituted phenyl, halogen-substituted phenyl, C1-C10Any one group of phenyl, naphthyl, pyrrolyl, furyl and thienyl substituted by alkoxy;
R3is phenyl, C1-C10Alkyl-substituted phenyl, halogen-substituted phenyl, C1-C10Alkoxy-substituted phenyl, naphthyl, and thienyl.
2. The 1,2, 5-polysubstituted imidazole derivatives according to claim 1, characterized in that:
wherein R is1Or R2Is p-methylphenyl, p-chlorophenyl, p-bromophenyl, p-methoxyphenyl, 3, 5-dichlorophenyl, 3, 5-dimethylphenyl, m-bromophenyl, m-methoxyphenyl, o-benzyloxyphenyl, o-fluorophenyl, 2-naphthyl, 2-pyrrolyl, 2-furyl or 2-thienyl;
R3is p-methylphenyl, p-chlorophenyl, p-bromophenyl, p-methoxyphenyl, 2-naphthyl or 2-thienyl.
3. A one-step synthesis method of 1,2, 5-polysubstituted imidazole derivatives according to claim 1, characterized in that:
taking styryl azide, aromatic aldehyde and aromatic amine as raw materials, rhodium acetate and phosphoric acid as catalysts, and an organic solvent as a solvent; placing the styryl azide, the aromatic aldehyde, the aromatic amine, the rhodium acetate and the phosphoric acid into a reaction bottle, adding an organic solvent to form a mixed solution, carrying out one-step reaction at the temperature of 90-110 ℃, and reacting for 12-18 h to obtain the 1,2, 5-polysubstituted imidazole derivative shown in the formula (1); the reaction process is shown as a reaction formula (I):
4. the one-step synthesis method of the 1,2, 5-polysubstituted imidazole derivatives according to claim 3, characterized in that: the phosphoric acid is racemic phosphoric acid containing a binaphthol skeleton, and is shown as a formula (2):
5. the one-step synthesis method of the 1,2, 5-polysubstituted imidazole derivatives according to claim 4, characterized in that: the molar ratio of the raw materials is styryl azide: aromatic aldehyde: aromatic amine: rhodium acetate: phosphoric acid = (2.0-3.0): (1.0-1.5): (1.0-1.5): (0.02-0.05): (0.1-0.2).
6. The one-step synthesis method of the 1,2, 5-polysubstituted imidazole derivatives according to claim 5, characterized in that: the molar ratio of the raw materials is styryl azide: aromatic aldehyde: aromatic amine: rhodium acetate: phosphoric acid =2.0:1.0:1.0:0.02: 0.1.
7. The one-step synthesis method of the 1,2, 5-polysubstituted imidazole derivatives according to claim 5, characterized in that: the molar ratio of the raw materials is styryl azide: aromatic aldehyde: aromatic amine: rhodium acetate: phosphoric acid =2.0:1.5:1.5:0.02: 0.1.
8. The one-step synthesis method of the 1,2, 5-polysubstituted imidazole derivatives according to claim 5, characterized in that: the molar ratio of the raw materials is styryl azide: aromatic aldehyde: aromatic amine: rhodium acetate: phosphoric acid =3.0:1.0:1.0:0.05: 0.2.
9. The one-step synthesis method of the 1,2, 5-polysubstituted imidazole derivatives according to any one of claims 3 to 8, characterized in that: the organic solvent adopts 1, 2-dichloroethane or aromatic hydrocarbon; wherein the aromatic hydrocarbon is selected from any one or more of toluene, chlorobenzene, xylene, fluorobenzene and anisole; reacting to obtain the 1,2, 5-polysubstituted imidazole derivative, and further comprising the steps of separation and purification; the separation and purification is to perform column chromatography by using a mixed solution of ethyl acetate and petroleum ether in a volume ratio of 1 (20-5).
10. The use and use of 1,2, 5-polysubstituted imidazole derivatives prepared according to the synthesis process as described in claim 1 or claim 3 in agrochemical, pharmaceutical and organic synthesis.
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