CN103755642A - Synthetic method of 2-aryl benzimidazole - Google Patents
Synthetic method of 2-aryl benzimidazole Download PDFInfo
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- CN103755642A CN103755642A CN201310578544.1A CN201310578544A CN103755642A CN 103755642 A CN103755642 A CN 103755642A CN 201310578544 A CN201310578544 A CN 201310578544A CN 103755642 A CN103755642 A CN 103755642A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
- C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
- C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
- C07D235/18—Benzimidazoles; Hydrogenated benzimidazoles with aryl radicals directly attached in position 2
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Abstract
The invention discloses a synthetic method of 2-aryl benzimidazole from aryl halogenated methane and 1,2-diamino aromatic hydrocarbon. 2-aryl benzimidazole compound has extensive biological activities and medicinal value. Aryl halogenated methane can be easily obtained from halogenation of methyl aromatic hydrocarbon and is cheap and easy to get. In the air, cuprous salt catalyzes aryl halogenated methane and 1,2-diamino aromatic hydrocarbon to react, so as to obtain the 2-aryl benzimidazole compound. The method has the advanategs of easily available raw materials, low cost and wide survivability of functional groups, and is suitable for industrial production.
Description
Technical field
The present invention relates to organic synthesis and medicine synthetic, is exactly specifically the synthetic method of 2-aryl benzimidazoles compound.
Background technology
2-aryl benzimidazoles compound is extensively present in natural product, and has biological activity and pharmaceutical use widely.
2-aryl benzimidazoles compound generally by phenylformic acid and derivative thereof synthesize (
j. Mol.Catal, A. 2007,
266, 198;
j.Heterocycl. Chem. 2007,
44, 1509;
bioorg. Med. Chem. Lett. 2011,
21, 1134; CN 103073503A).They also can by aromatic aldehyde and O-Phenylene Diamine (
tetrahedron Lett. 2008,
49, 6237;
j.Org. Chem. 2008,
73, 3848;
rSC Adv. 2013,
3, 9325) or 2-N-methyl-p-nitroaniline (
synthesis. 2005,
5, 47;
synth. Commun. 2007,
37,1375) synthetic.Nearest Ma(
angew. Chem. Int. Ed. 2007,
46, 2598) and Buchwald(
angew. Chem. Int. Ed. 2007,
46, 7509) and the linked reaction that developed the adjacent halogen ethanoyl aniline of copper and palladium catalysis and amine synthesizes.
[15-16]afterwards, Buchwald reported copper catalysis from N-aryl benzenyl amidine synthesize (
angew. Chem. Int. Ed. 2008,
47, 1932).In addition also have some adopt amidines as the report of the synthetic method of raw material (
j. Org. Chem. 2009,
74, 8719;
tetrahedron 2013,
69, 1717).
Cho reported the ruthenium by transalkylation catalyze and synthesize the method for benzoglyoxaline (
bull. Korean Chem. Soc. 2008,
29, 1097).Fan has reported cuprous chloride catalysis
n 1-benzyl-
n 2-aryl benzene-1, the method for the oxidisability Cyclization 1-aryl-2-Phenylbenzimidazole of 2-diamines (
chem. Commun.
2012,
48, 11775).
Recently Rangappa reported from the method with (carbon)-dibromo methylarenes synthesizing benzimidazole (
tetrahedron Lett. 2010,
51, 6493).But,, preparation difficulty, expensive unstable with (carbon)-dibromo methylarenes, and the alkali that need to consume doubling dose carrys out the Hydrogen bromide of neutralization reaction generation.
Summary of the invention
The synthetic method that the object of this invention is to provide a kind of 2-aryl benzimidazoles compound.
The present invention be take air as oxygenant, adds the weak base of 1 ~ 3 equivalent as acid binding agent, and cuprous salt catalysis aryl halide methane and 1,2-diamino aromatic hydrocarbons synthesize 2-aryl benzimidazoles compound.
The experimental implementation step of this synthetic method: 0.05 mmole cuprous salt, 1 of 1 mmole aryl halide methane, 1.5 ~ 3 mmoles, 2-diamino aromatic hydrocarbons, 1 ~ 2 mmole weak base, 4 milliliters of non-proton property intensive polar solvents add in test tube successively, and at 90 ~ 120 ℃, heated and stirred reaction is 10 ~ 24 hours.After cooling, be extracted with ethyl acetate, organic phase after drying concentrating under reduced pressure obtains crude product.Then the mixed solvent of sherwood oil and ethyl acetate of take is eluent, uses silica gel column chromatography separating purification crude product, obtains product 2-aryl benzimidazoles compound.Product process
1h NMR,
13the analytical data confirmations such as C NMR.
Embodiment
Below by embodiment, further set forth the present invention, therefore do not limit the present invention among described scope of embodiments.
embodiment 1
Cuprous bromide (0.05 mmole), sodium bicarbonate (1.2 mmole), benzyl bromine (1.0 mmole), O-Phenylene Diamine (3.0 mmole), dimethyl sulfoxide (DMSO) (4 milliliters) add in test tube successively, test tube are put in the oil bath pan of 120 ℃ to stirring reaction 24 hours.After cool to room temperature, add the shrend reaction of going out, with ethyl acetate (20 milliliters) extraction three times, organic phase water (20 milliliters) is washed once, anhydrous sodium sulfate drying, filtration for organic phase, and concentrating under reduced pressure obtains crude product.Then the mixed solvent (graded is from volume ratio 10/1 to 3/1) of sherwood oil and ethyl acetate of take is eluent, obtains 2-Phenylbenzimidazole, productive rate 83% with silica gel column chromatography separating purification.
embodiment 2
Examination on experimental operation, with embodiment 1, replaces 1.2 mmole sodium bicarbonates in embodiment 1 with 2 mmole sodium bicarbonates, obtains 2-Phenylbenzimidazole, productive rate 78%.
embodiment 3
Examination on experimental operation, with embodiment 1, replaces 1.2 mmole sodium bicarbonates in embodiment 1 with 2 mmole saleratus, obtains 2-Phenylbenzimidazole, productive rate 69%.
embodiment 4
Examination on experimental operation, with embodiment 1, replaces 1.2 mmole sodium bicarbonates in embodiment 1 with 2 mmole salt of wormwood, with DMF, replaces the dimethyl sulfoxide (DMSO) in embodiment 1, obtains 2-Phenylbenzimidazole, productive rate 65%.
embodiment 5
Examination on experimental operation, with embodiment 1, replaces 1.2 mmole sodium bicarbonates in embodiment 1 with 2 mmole sodium bicarbonates, with N, dinethylformamide replaces the dimethyl sulfoxide (DMSO) in embodiment 1, with cuprous iodide, replace the cuprous bromide in embodiment 1, obtain 2-Phenylbenzimidazole, productive rate 56%.
embodiment 6
Examination on experimental operation is with embodiment 1, and with 1.5 mmoles 1,2-diaminobenzene replaces 3.0 mmoles 1 in embodiment 1, and 2-diaminobenzene, obtains 2-Phenylbenzimidazole, productive rate 75%.
embodiment 7
Examination on experimental operation, with embodiment 1, so that methyl benzyl bromo is replaced to the benzyl bromine in embodiment 1, obtains 2-(4-aminomethyl phenyl) benzoglyoxaline, productive rate 74%.
embodiment 8
Examination on experimental operation, with embodiment 1, for the benzyl bromine in embodiment 1, obtains 2-(2-aminomethyl phenyl) benzoglyoxaline, productive rate 85% with adjacent methyl benzyl bromo.
embodiment 9
Examination on experimental operation, with embodiment 1, for the benzyl bromine in embodiment 1, obtains 2-(3-aminomethyl phenyl) benzoglyoxaline, productive rate 80% with a methyl benzyl bromo.
embodiment 10
Examination on experimental operation, with embodiment 1, so that methoxybenzyl bromo is replaced to the benzyl bromine in embodiment 1, obtains 2-(4-p-methoxy-phenyl) benzoglyoxaline, productive rate 86%.
embodiment 11
Examination on experimental operation, with embodiment 1, so that trifluoromethyl benzyl bromo is replaced to the benzyl bromine in embodiment 1, obtains 2-(4-trifluoromethyl) benzoglyoxaline, productive rate 70%.
embodiment 12
Examination on experimental operation, with embodiment 1, so that nitrobenzyl bromo is replaced to the benzyl bromine in embodiment 1, obtains 2-(4-nitrophenyl) benzoglyoxaline, productive rate 71%.
embodiment 13
Examination on experimental operation, with embodiment 1, for the benzyl bromine in embodiment 1, obtains 2-(3-Phenoxyphenyl) benzoglyoxaline, productive rate 82% with m-phenoxy benzyl bromo.
embodiment 14
Examination on experimental operation, with embodiment 1, replaces the benzyl bromine in embodiment 1 with a fluorobenzyl bromide, obtains 2-(3-fluorophenyl) benzoglyoxaline, productive rate 76%.
embodiment 15
Examination on experimental operation, with embodiment 1, replaces the benzyl bromine in embodiment 1 with adjacent fluorobenzyl bromide, obtains 2-(2-fluorophenyl) benzoglyoxaline, productive rate 76%.
embodiment 16
Examination on experimental operation, with embodiment 1, for the benzyl bromine in embodiment 1, obtains 2-(3-aminomethyl phenyl) benzoglyoxaline, productive rate 98% with a methyl benzyl bromo.
embodiment 17
Examination on experimental operation, with embodiment 1, for the benzyl bromine in embodiment 1, obtains 2-(3-trifluoromethyl) benzoglyoxaline, productive rate 83% with m-trifluoromethyl benzyl chloro.
embodiment 18
Examination on experimental operation, with embodiment 1, so that benzyl chloride chloro is replaced to the benzyl bromine in embodiment 1, obtains 2-(4-chloro-phenyl-) benzoglyoxaline, productive rate 76%.
embodiment 19
Examination on experimental operation, with embodiment 1, for the benzyl bromine in embodiment 1, obtains 2-(4-chloro-phenyl-) benzoglyoxaline, productive rate 82% with a cyano group benzyl bromo.
embodiment 20
Examination on experimental operation is with embodiment 1, and with 4-methoxyl group-1,2-diaminobenzene replaces the O-Phenylene Diamine in embodiment 1, obtains 2-phenyl-4-methoxyl group benzo imidazoles, productive rate 87%.
embodiment 21
Examination on experimental operation is with embodiment 1, and with 4,5-dimethyl-1,2-diaminobenzene replaces the O-Phenylene Diamine in embodiment 1, obtains 2-phenyl-4,5-dimethylbenzimidazole, productive rate 87%.
embodiment 22
Examination on experimental operation is with embodiment 1, and with 4-nitro-1,2-diaminobenzene replaces the O-Phenylene Diamine in embodiment 1, obtains 2-phenyl-4-nitrobenzimidazole, productive rate 88%.
embodiment 23
Examination on experimental operation is with embodiment 1, and with 4-Trifluoromethyl-1,2-diaminobenzene replaces the O-Phenylene Diamine in embodiment 1, obtains 2-phenyl-4-trifluoro methyl benzimidazole, productive rate 90%.
embodiment 24
Examination on experimental operation is with embodiment 1, and chloro-1 with 4-, 2-diaminobenzene replaces the O-Phenylene Diamine in embodiment 1, obtains 2-phenyl-4-chloro benzimidazole, productive rate 87%.
embodiment 25
Examination on experimental operation, with embodiment 1, with 90 ℃ of 120 ℃ of replacing in embodiment 1, obtains 2-Phenylbenzimidazole, productive rate 56%.
embodiment 26
Examination on experimental operation is with embodiment 1, and with replacing in embodiment 1 for 10 hours 24 hours obtain 2-Phenylbenzimidazole, productive rate 48%.
Claims (2)
1. a synthetic method for 2-aryl benzimidazoles compound, its feature is that cuprous salt catalysis aryl halide methane and 1,2-diamino aromatic hydrocarbons react under air and obtains 2-aryl benzimidazoles compound.
2. the synthetic method of a kind of 2-aryl benzimidazoles compound claimed in claim 1, cuprous salt is cuprous bromide or cuprous iodide, aryl halomethane ﹕ 1, the mol ratio of 2-diamino Fang Ting ﹕ Ruo Jian ﹕ cuprous salt is 1 ﹕ 1.5 ~ 3 ﹕ 1 ~ 2 ﹕ 0.05, weak base is sodium bicarbonate, saleratus or sodium carbonate, under air, react 90 ~ 120 ℃ of temperature, 10 ~ 24 hours reaction times.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106946862A (en) * | 2017-03-31 | 2017-07-14 | 刘雪静 | 1 alkane, 6 methyl 5 nitro 1H benzos [D] glyoxaline compound and preparation method thereof |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2002101073A2 (en) * | 2001-06-13 | 2002-12-19 | Genesoft Pharmaceuticals, Inc. | Aryl-benzimidazole compounds having antiinfective activity |
| CN101759686A (en) * | 2010-01-22 | 2010-06-30 | 浙江理工大学 | Synthesizing method and application of 2-substituted aryl-1-substituted benzyl benzimidazole compound |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2002101073A2 (en) * | 2001-06-13 | 2002-12-19 | Genesoft Pharmaceuticals, Inc. | Aryl-benzimidazole compounds having antiinfective activity |
| CN101759686A (en) * | 2010-01-22 | 2010-06-30 | 浙江理工大学 | Synthesizing method and application of 2-substituted aryl-1-substituted benzyl benzimidazole compound |
Non-Patent Citations (3)
| Title |
|---|
| DEZHI QIU ET AL.: "Synthesis of benzimidazoles by copper-catalyzed aerobic oxidative domino reaction of 1,2-diaminoarenes and arylmethyl halides", 《APPL. ORGANOMETAL. CHEM.》, vol. 28, 6 December 2013 (2013-12-06), pages 109 - 112 * |
| GANESH R. JADHAV ET AL.: "Ammonium metavanadate: A novel catalyst for synthesis of 2-substituted benzimidazole derivatives", 《CHINESE CHEMICAL LETTERS》, vol. 20, 31 December 2009 (2009-12-31), pages 292 - 295 * |
| MI-HYUN KIM ET AL.: "Syntheses and biological evaluation of 1-heteroaryl-2-aryl-1H-benzimidazole derivatives as c-Jun N-terminal kinase inhibitors with neuroprotective effects", 《BIOORGANIC & MEDICINAL CHEMISTRY》, vol. 21, 21 February 2013 (2013-02-21), pages 2271 - 2285 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106946862A (en) * | 2017-03-31 | 2017-07-14 | 刘雪静 | 1 alkane, 6 methyl 5 nitro 1H benzos [D] glyoxaline compound and preparation method thereof |
| CN106946862B (en) * | 2017-03-31 | 2019-09-03 | 枣庄学院 | 1- alkane -6- methyl-5-nitro -1H- benzo [D] glyoxaline compound and preparation method thereof |
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