CN103254134B - A kind of synthetic method of polysubstituted imidazoles - Google Patents
A kind of synthetic method of polysubstituted imidazoles Download PDFInfo
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- CN103254134B CN103254134B CN201210219933.0A CN201210219933A CN103254134B CN 103254134 B CN103254134 B CN 103254134B CN 201210219933 A CN201210219933 A CN 201210219933A CN 103254134 B CN103254134 B CN 103254134B
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- cuprous iodide
- imidazoles
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- benzyl
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- 0 *N(CC1=C*C=CC=C1)C(c1ccccc1)=* Chemical compound *N(CC1=C*C=CC=C1)C(c1ccccc1)=* 0.000 description 1
- RIDBYNZHFMHZCP-UHFFFAOYSA-N NCC1=CC=CCC1=[IH] Chemical compound NCC1=CC=CCC1=[IH] RIDBYNZHFMHZCP-UHFFFAOYSA-N 0.000 description 1
Abstract
The invention reside in the synthetic method disclosing a kind of polysubstituted imidazoles, it is characterized in that, comprise the following steps: methyl phenyl ketone is mixed with the ratio of benzylamine in 1:3; Under cuprous iodide and boron trifluoride diethyl etherate concerted catalysis effect, by mixture stirring reaction 24 hours under oxygen, solvent-free and 40 DEG C of temperature condition; TLC detects; Column chromatography for separation obtains target product.This invention does not need additionally to add solvent, decreases using and discharging of organic solvent; The starting raw material of this invention is cheap and easy to get, has saved synthesis cost; This invention can the conversion of realization response under the catalytic condition of cuprous iodide and oxygen, and catalytic condition is simple; This invention is carried out under 40 DEG C of temperature condition, and temperature is low, and reaction conditions is gentle.
Description
Technical field
The invention belongs to organic chemistry and medicinal chemistry art, particularly a kind of synthetic method of polysubstituted imidazoles.
Background technology
Polysubstituted imidazoles is the important nitrogen heterocyclic organic compound of a class, and its skeleton is extensively present in some natural products, drug molecule, functional high molecule material and organic synthesis intermediate.
That glyoxaline compound is applied in biological medicine and extensive, such as:
cimetidine(1) (antiulcer drug);
ketoconazole(2) (antifungal drug,
wilson and Gisvold ' s Textbook of Organic Medicinal and Pharmaceutical Chemistry, 10th ed.; Delgado, J. N., Remers, W. A., Eds.; Lippincott-Raven:Philadelphia, PA, 1998.);
apoptozole(3) (treatment cystic fibrosis,
j. Am. Chem. Soc.2011,
133, 20267 – 20276.).
From having document at present, the most frequently used method is:
(1) 1,2-diketone, the cyclic condensation of α halogenated ketone and methane amide,
Chem. Ber. 1953,86,88.
(2) 1,2-diketone, the cyclic condensation of aldehyde and ammonia, (a)
ber.Dtsch.Chem.Ges. 1882,15,1268.(b)
ber. Dtsch. Chem. Ges. 1882,15,1493. (c)
justus Liebigs Ann. Chem. 1858,17,199.
(3) cyclic condensation of α halogenated ketone and amidine,
ber. Dtsch. Chem. Ges. 1901,34,637.
(4) cyclic condensation of isonitrile and imines, (a)
j. Org.Chem. 1977,42,1153.(b)
org. React.2001,57,417.
But these methods often need to use highly basic, or carry out at very high temperatures, often there is more by product to generate simultaneously.Therefore, the exploitation of the novel method for synthesizing of polysubstituted glyoxaline compound is organic chemistry and pharmaceutical chemical hot research field always.
Existing technology of preparing has following shortcoming:
1, need to use strong acid or highly basic, some temperature of reaction are higher;
2, the synthetic method report for the polysubstituted imidazoles of 1,2,4-is less;
3, the more difficult preparation of reaction substrate;
4, catalyst system needs additionally to add organic solvent;
5, the catalyzer had is toxic;
6, generate that other by product is more or productive rate is lower.
These not foot point all limit its synthesis on application.Therefore, the synthetic route of synthesizing polysubstituted imidazoles with raw material cheap and easy to get in simple gentle next footwork of condition has very large investigation and application prospect.
Summary of the invention
The object of the invention is to overcome the deficiencies in the prior art, provide a kind of with raw material cheap and easy to get gentleness catalytic condition next step synthesize the method for polysubstituted imidazoles.
For solving the problems of the technologies described above, realizing above-mentioned technique effect, present invention employs following technical scheme:
A synthetic method for polysubstituted imidazoles, its reaction equation is as follows:
Specifically comprise the following steps:
Methyl phenyl ketone mixes with the ratio of benzylamine in 1:3 by step 1);
Step 2) under cuprous iodide and boron trifluoride diethyl etherate concerted catalysis effect, by mixture stirring reaction 24 hours under oxygen, solvent-free and 40 DEG C of temperature condition;
Step 3) TLC detects;
Step 4) column chromatography for separation obtains target product.
Further, described methyl phenyl ketone can be the one in methyl phenyl ketone, fluoro acetophenone, chloro-acetophenone, bromoacetophenone, nitro-acetophenone, trifluoromethyl acetophenone, methyl acetophenone, p-methoxy-acetophenone, 1,2-diphenylethan, 2,2-dimethyl-2-butanones.
Further, described benzylamine can be benzylamine, to fluorine Bian amine, to chlorine Bian amine, to methyl Bian amine, to methoxyl group Bian amine, to a kind of in tertiary butyl Bian amine.
Principle of the present invention is:
The present invention is at CuI/O
2, BF
3et
2under O effect, methyl phenyl ketone and benzylamine solvent-free, 40
onamely C agitation condition higher yields can obtain polysubstituted glyoxaline compound in lower 24 hours, and have cheaper starting materials to be easy to get, catalytic condition is simple, gentle, convenient post-treatment, and productive rate is advantages of higher comparatively.Simultaneously in conditional filtering process, to different additive FeCl
3, InCl
3, I
2, HOAc, BF
3et
2o all can obtain expected results, but BF
3et
2o effect is optimum, and between ratio 1:1 to 1:3 different between methyl phenyl ketone from benzylamine, 1:3 is optimum, different temperature 25-80
oc scope all can obtain target product, and wherein preferably 40
oc is optimum, screens, and seeks best reaction conditions with this.
Beneficial effect of the present invention is:
1, this invention does not need additionally to add solvent, decreases using and discharging of organic solvent;
2, the starting raw material of this invention is cheap and easy to get, has saved synthesis cost;
3, this invention can the conversion of realization response under the catalytic condition of cuprous iodide and oxygen, and catalytic condition is simple;
4, this invention is carried out under 40 DEG C of temperature condition, and temperature is low, and reaction conditions is gentle.
Embodiment
Below in conjunction with specific embodiment, the present invention is described in further detail.
A synthetic method for polysubstituted imidazoles, its reaction equation is as follows:
embodiment one:the synthesis of 1-benzyl-2,4-diphenyl-imidazole
Take 2mmol methyl phenyl ketone (0.242 gram), the Bian amine (0.642 gram) of 3mmol, 0.04mmol cuprous iodide (0.076 gram), 0.02mmol boron trifluoride diethyl etherate (0.028 gram) is in the Schlenk-tube of 25mL, in oxygen atmosphere, stir 24 hours at 40 DEG C, column chromatography for separation obtains 0.442g1-benzyl-2,4-diphenyl-imidazole sterling, productive rate 71%.
embodiment two:1-benzyl-2-phenyl-4-is to the synthesis of fluorophenyl imidazoles
Take 2mmol to fluoro acetophenone (0.276 gram), the Bian amine (0.642 gram) of 3mmol, 0.04mmol cuprous iodide (0.076 gram), 0.02mmol boron trifluoride diethyl etherate (0.028 gram) is in the Schlenk-tube of 25mL, in oxygen atmosphere, stir 24 hours at 40 DEG C, column chromatography for separation obtains 0.327g1-benzyl-2-phenyl-4-to fluorophenyl imidazoles sterling, productive rate 50%.
embodiment three:the synthesis of 1-benzyl-2-phenyl-4-rubigan imidazoles
Take 2mmol parachloroacetophenone (0.3092 gram), the Bian amine (0.642 gram) of 3mmol, 0.04mmol cuprous iodide (0.076 gram), 0.02mmol boron trifluoride diethyl etherate (0.028 gram) is in the Schlenk-tube of 25mL, in oxygen atmosphere, stir 24 hours at 40 DEG C, column chromatography for separation obtains 0.368g1-benzyl-2-phenyl-4-rubigan imidazoles sterling, productive rate 54%.
embodiment four:1-benzyl-2-phenyl-4-is to the synthesis of bromophenyl imidazoles
Take 2mmol parabromoacetophenone (0.3981 gram), the Bian amine (0.642 gram) of 3mmol, 0.04mmol cuprous iodide (0.076 gram), 0.02mmol boron trifluoride diethyl etherate (0.028 gram) is in the Schlenk-tube of 25mL, in oxygen atmosphere, stir 24 hours at 40 DEG C, column chromatography for separation obtains 0.538g1-benzyl-2-phenyl-4-to bromophenyl imidazoles sterling, productive rate 69%.
embodiment five:the synthesis of 1-benzyl-2-phenyl-4-p-nitrophenyl imidazoles
Take 2mmol p-nitroacetophenone (0.3301 gram), the Bian amine (0.642 gram) of 3mmol, 0.04mmol cuprous iodide (0.076 gram), 0.02mmol boron trifluoride diethyl etherate (0.028 gram) is in the Schlenk-tube of 25mL, in oxygen atmosphere, stir 24 hours at 40 DEG C, column chromatography for separation obtains 0.537g1-benzyl-2-phenyl-4-p-nitrophenyl imidazoles sterling, productive rate 76%.
embodiment six:the synthesis of 1-benzyl-2-phenyl-4-p-trifluoromethyl phenyl imidazoles
Take 2mmol to trifluoromethyl acetophenone (0.3761 gram), the Bian amine (0.642 gram) of 3mmol, 0.04mmol cuprous iodide (0.076 gram), 0.02mmol boron trifluoride diethyl etherate (0.028 gram) is in the Schlenk-tube of 25mL, in oxygen atmosphere, stir 24 hours at 40 DEG C, column chromatography for separation obtains 0.538g1-benzyl-2-phenyl-4-p-trifluoromethyl phenyl imidazoles sterling, productive rate 58%.
embodiment seven:the synthesis of 1-benzyl-2-phenyl-4-p-methylphenyl imidazoles
Take 2mmol p-methyl aceto phenone (0.2681 gram), the Bian amine (0.642 gram) of 3mmol, 0.04mmol cuprous iodide (0.076 gram), 0.02mmol boron trifluoride diethyl etherate (0.028 gram) is in the Schlenk-tube of 25mL, in oxygen atmosphere, stir 24 hours at 40 DEG C, column chromatography for separation obtains 3557g1-benzyl-2-phenyl-4-p-methylphenyl imidazoles sterling, productive rate 55%.
embodiment eight:the synthesis of 1-benzyl-2-phenyl-4-p-methoxyphenyl imidazoles
Take 2mmol p-methoxy-acetophenone (0.3001 gram), the Bian amine (0.642 gram) of 3mmol, 0.04mmol cuprous iodide (0.076 gram), 0.02mmol boron trifluoride diethyl etherate (0.028 gram) is in the Schlenk-tube of 25mL, in oxygen atmosphere, stir 24 hours at 40 DEG C, column chromatography for separation obtains 0.538g1-benzyl-2-phenyl-4-p-methoxyphenyl imidazoles sterling, productive rate 54%.
embodiment nine:1-is to the synthesis of luorobenzyl-2-to fluorophenyl-4-phenylimidazole
Take 2mmol methyl phenyl ketone (0.242 gram), 3mmol to fluorine Bian amine (0.7511 gram), 0.04mmol cuprous iodide (0.076 gram), 0.02mmol boron trifluoride diethyl etherate (0.028 gram) is in the Schlenk-tube of 25mL, in oxygen atmosphere, stir 24 hours at 40 DEG C, column chromatography for separation obtains 0.3617g1-to luorobenzyl-2-to fluorophenyl-4-phenylimidazole sterling, productive rate 52%.
embodiment ten:the synthesis of 1-p-chlorobenzyl-2-rubigan-4-phenylimidazole
Take 2mmol methyl phenyl ketone (0.242 gram), 3mmol to chlorine Bian amine (0.8462 gram), 0.04mmol cuprous iodide (0.076 gram), 0.02mmol boron trifluoride diethyl etherate (0.028 gram) is in the Schlenk-tube of 25mL, in oxygen atmosphere, stir 24 hours at 40 DEG C, column chromatography for separation obtains 0.2926g1-p-chlorobenzyl-2-rubigan-4-phenylimidazole sterling, productive rate 39%.
embodiment 11:1-is to the synthesis of methyl-benzyl-2-p-methylphenyl-4-phenylimidazole
Take 2mmol methyl phenyl ketone (0.242 gram), 3mmol to methyl Bian amine (0.7265 gram), 0.04mmol cuprous iodide (0.076 gram), 0.02mmol boron trifluoride diethyl etherate (0.028 gram) is in the Schlenk-tube of 25mL, in oxygen atmosphere, stir 24 hours at 40 DEG C, column chromatography for separation obtains 0.222g1-to methyl-benzyl-2-p-methylphenyl-4-phenylimidazole sterling, productive rate 34%.
embodiment 12:1-is to the synthesis of methoxy-benzyl-2-p-methoxyphenyl-4-phenylimidazole
Take 2mmol methyl phenyl ketone (0.242 gram), 3mmol to methoxyl group Bian amine (0.8225 gram), 0.04mmol cuprous iodide (0.076 gram), 0.02mmol boron trifluoride diethyl etherate (0.028 gram) is in the Schlenk-tube of 25mL, in oxygen atmosphere, stir 24 hours at 40 DEG C, column chromatography for separation obtains 0.178g1-to methoxy-benzyl-2-p-methoxyphenyl-4-phenylimidazole sterling, productive rate 22%.
embodiment 13:1-is to the synthesis of t-butylbenzyl-2-to tert-butyl-phenyl-4-phenylimidazole
Take 2mmol methyl phenyl ketone (0.242 gram), 3mmol to tertiary butyl Bian amine (0.9788 gram), 0.04mmol cuprous iodide (0.076 gram), 0.02mmol boron trifluoride diethyl etherate (0.028 gram) is in the Schlenk-tube of 25mL, in oxygen atmosphere, stir 24 hours at 40 DEG C, column chromatography for separation obtains 0.591g1-to t-butylbenzyl-2-to tert-butyl-phenyl-4-phenylimidazole sterling, productive rate 70%.
embodiment 14:the synthesis of 1-benzyl-2,4,5-triphenylimidazolyl
Take 2mmol1,2-diphenylethan (0.39222 gram), the Bian amine (0.642 gram) of 3mmol, 0.04mmol cuprous iodide (0.076 gram), 0.02mmol boron trifluoride diethyl etherate (0.028 gram) is in the Schlenk-tube of 25mL, in oxygen atmosphere, stir 24 hours at 40 DEG C, column chromatography for separation obtains 0.1257g1-benzyl-2,4,5-triphenylimidazolyl sterling, productive rate 17%.
embodiment 15:the synthesis of 1-benzyl-2-phenyl-4-t-butyl imidazole
Take 2mmol2,2-dimethyl-2-butanone (0.2002 gram), the Bian amine (0.642 gram) of 3mmol, 0.04mmol cuprous iodide (0.076 gram), 0.02mmol boron trifluoride diethyl etherate (0.028 gram), in the Schlenk-tube of 25mL, in oxygen atmosphere, stirs 24 hours at 40 DEG C, column chromatography for separation obtains 0.3219g1-benzyl-2-phenyl-4-t-butyl imidazole sterling, productive rate 56%.
The foregoing is only the preferred embodiments of the present invention, be not limited to the present invention, for a person skilled in the art, the present invention can have various modifications and variations.Within the spirit and principles in the present invention all, any amendment done, equivalent replacement, improvement etc., all should be included within protection scope of the present invention.
Claims (1)
1. a synthetic method for polysubstituted imidazoles, is characterized in that, its reaction equation is as follows:
Specifically comprise the following steps: methyl phenyl ketone mixes with the ratio of benzylamine in 1:3 by step 1); Step 2) under cuprous iodide and boron trifluoride diethyl etherate concerted catalysis effect, by mixture stirring reaction 24 hours under oxygen, solvent-free and 40 DEG C of temperature condition; Step 3) TLC detects; Step 4) column chromatography for separation obtains target product; Wherein substituent R 1 is H, F, Cl, Br, NO
2, CF
3, CH
3,p-CH
3one in O; Substituent R 2 is H, p-F, p-Cl, p-CH
3, p-CH
3o, p-C (CH
3)
3in one.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101193867A (en) * | 2004-12-01 | 2008-06-04 | Osi医药有限公司 | N-substituted benzimidazolyl c-Kit inhibitors and combinatorial benzimidazole library |
| WO2008105565A1 (en) * | 2007-02-26 | 2008-09-04 | Industry-Academic Cooperation Foundation, Yonsei University | Imidazole derivatives that induce apoptosis and their therapeutic uses |
| CN101492480A (en) * | 2009-01-16 | 2009-07-29 | 四川大学 | Synthesis of 2-(4-beta-D-pyran Azloglycoside-phenyl)-4,5-diaryl imidazole |
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2012
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101193867A (en) * | 2004-12-01 | 2008-06-04 | Osi医药有限公司 | N-substituted benzimidazolyl c-Kit inhibitors and combinatorial benzimidazole library |
| WO2008105565A1 (en) * | 2007-02-26 | 2008-09-04 | Industry-Academic Cooperation Foundation, Yonsei University | Imidazole derivatives that induce apoptosis and their therapeutic uses |
| CN101492480A (en) * | 2009-01-16 | 2009-07-29 | 四川大学 | Synthesis of 2-(4-beta-D-pyran Azloglycoside-phenyl)-4,5-diaryl imidazole |
Non-Patent Citations (3)
| Title |
|---|
| CuI/BF3 3 Et2O Cocatalyzed Aerobic Dehydrogenative Reactions of Ketones with Benzylamines: Facile Synthesis of Substituted Imidazoles;Zhong-Jian Cai，等;《ORGANIC LETTERS》;20121120;第14卷(第23期);第6068–6071页 * |
| Huawen Huang,等.Practical Synthesis of Polysubstituted Imidazoles via Iodine-Catalyzed Aerobic Oxidative Cyclization of Aryl Ketones and Benzylamines.《Adv. Synth. Catal.》.2012,第355卷第170-180页. * |
| 张百群,等.碘催化的串联氧化环化反应合成多取代咪唑.《化学学报》.2012,第70卷第2408-2411页. * |
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