CN102942555A - Preparation method of aromatic group-substituted thiophene - Google Patents
Preparation method of aromatic group-substituted thiophene Download PDFInfo
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- CN102942555A CN102942555A CN2012103880019A CN201210388001A CN102942555A CN 102942555 A CN102942555 A CN 102942555A CN 2012103880019 A CN2012103880019 A CN 2012103880019A CN 201210388001 A CN201210388001 A CN 201210388001A CN 102942555 A CN102942555 A CN 102942555A
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Abstract
The present invention discloses a preparation method for a class of aromatic group-substituted thiophene. The method includes: adding an organic solvent, aromatic bromide, and a dimethyl(3-thienyl)aluminum or dimethyl(2-thienyl)aluminum reagent to palladium acetate and tri(o-methylphenyl)phosphorus under the protection of argon, reacting at room temperature for no less than 5 hours, adding distilled water to terminate the reaction, extracting, drying, removing the solvent under reduced pressure to get the crude product, and then separating by column chromatography to obtain the product. Compared with the prior art, the preparation method makes use of palladium to catalyze the coupled reaction between the aromatic bromides and the thiophene aluminum reagent to prepare thiophene compounds containing various aromatic substituents (or heteroaromatic groups), and has the advantages of mild reaction conditions, rapid reaction rate, high yield, no alkali added in the reaction process, etc.
Description
Technical field
The present invention relates to the preparation method of a class aromatic base substituted thiophene, exactly is a class contains the substituted thiophene of aromatic base (or assorted aromatic base) in the 3-position (or 2-position) of thiophene preparation method.
Background technology
The substituted thiophene of aromatic base or assorted aromatic base is widely used in synthetic medicine, agricultural chemicals, dyestuff and Polythiophene compound etc.The linked reaction of transition metal-catalyzed thiophene halogenide and aromatic base boric acid, aromatic base zinc, aryl Grignard reagent is common method (the J. P. Wolfe of synthetic this compounds, R. A. Singer, B. H. Yang, S. L. Buchwald. J. Am. Chem. Soc. 1999,121,9550-9561; C. Dai, G. C. Fu. J. Am. Chem. Soc. 2001,123,2719-2724).Because the kind of arylide reagent is limited, few by 2 aryl compound kinds that contain thiophene that this method is synthetic.Therefore, caused organic chemist's attention by transition metal-catalyzed thiophene metal reagent and the halid linked reaction of aromatic base (or assorted aromatic base).Palladium catalysis thienyl acid reagent (K. Billingsley and S. L. Buchwald. J. Am. Chem. Soc. 2007,129,3358-3366), thienyl zincon (X. Wu and R. D. Rieke. J. Org. Chem. 1996,60,6658-6659; M. R. Luzung, J. S. Patel, J. Yin, J. Org. Chem. 2010,75,8330-8332) and thienyl Grignard reagent (M. G. Organ, M. Abdel-Hadi, S. Avola, N. Hadei, J. Nasielski, C. J. O'Brien, and C. Valente. Chem. Eur. J. 2007,13 150-157) has been used to preparation various substituted aromatic bases (or assorted aromatic base) thiophene compound widely with the halid linked reaction of aromatic base.
Summary of the invention
The purpose of this invention is to provide a kind of new 3-(assorted) aromatic base substituted thiophene compound and 2-(be assorted) preparation method of aromatic base substituted thiophene compound.
Technical problem to be solved by this invention is: the preparation method of a class aromatic base substituted thiophene, with palladium and three (o-methyl-phenyl-) phosphorus under argon shield, add organic solvent, aromatic bromide, dimethyl (3-thiophene) aluminium or dimethyl (2-thiophene) aurin tricarboxylic acid, after room temperature reaction is not less than reaction in 5 hours, add the distilled water termination reaction, extraction, drying, removal of solvent under reduced pressure obtains thick product, obtains product by column chromatography for separation again;
The mol ratio of palladium, three (o-methyl-phenyl-) phosphorus, aromatic bromide, dimethyl (3-thiophene) aluminium or dimethyl (2-thiophene) aurin tricarboxylic acid is 1:2:50-65.
Described aromatic bromide is that 2-, 3-or 4-position are the substituted-phenyl bromine of methyl, methoxyl group, nitro or itrile group.
Described aromatic bromide is 2-bromo pyrimi piperidine, 4-bromo pyrimi piperidine, 2-bromo thiazole or 3-bromoquinoline.
Described organic solvent is toluene, normal hexane, ether or tetrahydrofuran (THF).
Described dimethyl (3-thiophene) aluminium or by the following method preparation:
At-70～-50 ° of C, in the diethyl ether solution of 3 bromo thiophene, add n-Butyl Lithium, be incubated 2-3 hour, add again AlMe
2Cl is incubated 3-4 hour, and reaction is taken out diethyl ether solution after finishing, and obtains weak yellow liquid, extracts with normal hexane, concentrated getting final product;
3 bromo thiophene, n-Butyl Lithium, AlMe
2The mol ratio of Cl is 1:1:1.
Described dimethyl (2-thiophene) aurin tricarboxylic acid prepares by the following method:
-20～0
oC in the diethyl ether solution of 2-bromothiophene, adds n-Butyl Lithium, is incubated 2-3 hour, adds AlMe again
2Cl is incubated 3-4 hour, and reaction is taken out diethyl ether solution after finishing, and obtains weak yellow liquid, extracts with normal hexane, concentrated getting final product;
2-bromothiophene, n-Butyl Lithium, AlMe
2The mol ratio of Cl is 1:1:1.
The structure of the 3-aromatic base of described aromatic base substituted thiophene (or assorted aromatic base) substituted thiophene compound or 2-aromatic base (or assorted aromatic base) substituted thiophene compound is as follows:
In the formula, R
1Be aromatic base, substituted aromatic base, assorted aromatic base;
Described substituted aromatic base substituting group is methyl, methoxyl group, nitro or itrile group; Substituting group is 2-, 3-or 4-position.
Described assorted aromatic base is 2-pyrimidine, 4-pyrimidine, 2-thiazole or 3-quinoline.
The divalence palladium is reduced to the zeroth order palladium by organophosphorus first in this reaction process, then zeroth order palladium and aromatic bromide generation oxidative addition, form new carbon-palladium key, with dimethyl (3-thiophene) aluminium or dimethyl (3-thiophene) aluminium the exchange metallization reaction occurs again, eliminate reaction through reduction again and obtain product, the divalence palladium is reduced to the zeroth order palladium and continues catalytic cycle.
The present invention utilizes the linked reaction of palladium catalysis aromatic bromide and thiophene aurin tricarboxylic acid to prepare to contain various aromatic substituents (or assorted aromatic base) thiophene compound, have the reaction conditions gentleness, and speed of reaction is fast, and productive rate is high, and reaction process need not to add the advantages such as alkali.
Embodiment
The present invention is described in detail below in conjunction with embodiment
Embodiment 1
At-70～-50 ° of C, in the 60 mL diethyl ether solutions of 3 bromo thiophene (6.52 g, 40 mmol), drip at leisure the n-Butyl Lithium of 16 mL, 2.5 M, kept this temperature 3 hours.Add afterwards AlMe
2Cl (40 mmol), the white suspension solution that becomes colorless keeps this temperature 1 h, removes afterwards low temperature.Reaction is taken out diethyl ether solution after finishing, and obtains weak yellow liquid, with 40 mL n-hexane extraction products.Concentrated hexane solution obtains weak yellow liquid, obtains dimethyl (3-thiophene) aluminium.
Embodiment 2
-20～0
oC in the 60 mL diethyl ether solutions of 2-bromothiophene (6.52 g, 40 mmol), drips the n-Butyl Lithium of 16 mL, 2.5 M at leisure, continues 0 ° of C reaction 3 hours.The AlMe that adds afterwards 2.1 M
2Cl (18.4 mL, 40 mmol), the white suspension solution that becomes colorless keeps this temperature 1 h, removes afterwards low temperature.Reaction is taken out diethyl ether solution after finishing, and obtains weak yellow liquid, with 40 mL normal hexane extraction products.Concentrated hexane solution obtains weak yellow liquid, obtains dimethyl (2-thiophene) aluminium.
Embodiment 3
Palladium (0.02 mmol) and tri-o-tolyl phosphine (0.04 mmol) are joined in the reaction flask, vacuumize half an hour, under argon shield, add successively 2 mL toluene, 1 mmol aromatic bromide and 1.3 mmol 3-thiophene aurin tricarboxylic acids afterwards.Stirring reaction 5 hours (TLC monitoring) at room temperature.Add distilled water (10 mL) termination reaction after the reaction, with ethyl acetate extraction (30 mL * 3), anhydrous magnesium sulfate drying, removal of solvent under reduced pressure obtains thick product, take the mixed solvent of sherwood oil: ethyl acetate=100:1 as developping agent, obtain product by column chromatography for separation.
The linked reaction of table 1 3-thiophene aurin tricarboxylic acid and aromatic bromide
Embodiment 4:
Except palladium is that 0.04 mmol, tri-o-tolyl phosphine are 0.08 mmol, outer, all the other are identical with embodiment 3.
Table 2:
Embodiment 5
Palladium (0.02 mmol) and tri-o-tolyl phosphine (0.04 mmol) are joined in the reaction flask, vacuumize half an hour, under argon shield, add successively 2 mL toluene, 1 mmol aromatic bromide and 1.3 mmol 2-thiophene aurin tricarboxylic acids afterwards.Stirring reaction 5 hours (TLC monitoring) at room temperature.Add distilled water (10 mL) termination reaction after the reaction, with ethyl acetate extraction (30 mL * 3), anhydrous magnesium sulfate drying, removal of solvent under reduced pressure obtains thick product, take the mixed solvent of sherwood oil: ethyl acetate=100:1 as developping agent, obtain product by column chromatography for separation.
The linked reaction of table 3 2-thiophene aurin tricarboxylic acid and aromatic bromide
Embodiment 6:
Except palladium is that 0.04 mmol, tri-o-tolyl phosphine are 0.08 mmol, outer, all the other are identical with embodiment 5.
Table 4:
Claims (9)
1. the preparation method of a class aromatic base substituted thiophene, it is characterized in that: with palladium and three (o-methyl-phenyl-) phosphorus under argon shield, add organic solvent, aromatic bromide, dimethyl (3-thiophene) aluminium or dimethyl (2-thiophene) aurin tricarboxylic acid, after room temperature reaction is not less than reaction in 5 hours, add the distilled water termination reaction, extraction, drying, removal of solvent under reduced pressure obtains thick product, obtains product by column chromatography for separation again;
The mol ratio of palladium, three (o-methyl-phenyl-) phosphorus, aromatic bromide, dimethyl (3-thiophene) aluminium or dimethyl (2-thiophene) aurin tricarboxylic acid is 1:2:50-65.
2. the preparation method of a class aromatic base substituted thiophene according to claim 1 is characterized in that:
Described aromatic bromide is that 2-, 3-or 4-position are the substituted-phenyl bromine of methyl, methoxyl group, nitro or itrile group.
3. the preparation method of a class aromatic base substituted thiophene according to claim 1 is characterized in that:
Described aromatic bromide is 2-bromo pyrimi piperidine, 4-bromo pyrimi piperidine, 2-bromo thiazole or 3-bromoquinoline.
4. the preparation method of a class aromatic base substituted thiophene according to claim 1 is characterized in that:
Described organic solvent is toluene, normal hexane, ether or tetrahydrofuran (THF).
5. the preparation method of a class aromatic base substituted thiophene according to claim 1 is characterized in that:
Described dimethyl (3-thiophene) aluminium or by the following method preparation:
At-70～-50 ° of C, in the diethyl ether solution of 3 bromo thiophene, add n-Butyl Lithium, be incubated 2-3 hour, add again AlMe
2Cl is incubated 3-4 hour, and reaction is taken out diethyl ether solution after finishing, and obtains weak yellow liquid, extracts with normal hexane, concentrated getting final product;
3 bromo thiophene, n-Butyl Lithium, AlMe
2The mol ratio of Cl is 1:1:1.
6. the preparation method of a class aromatic base substituted thiophene according to claim 1 is characterized in that:
Described dimethyl (2-thiophene) aurin tricarboxylic acid prepares by the following method:
-20～0
oC in the diethyl ether solution of 2-bromothiophene, adds n-Butyl Lithium, is incubated 2-3 hour, adds AlMe again
2Cl is incubated 3-4 hour, and reaction is taken out diethyl ether solution after finishing, and obtains weak yellow liquid, extracts with normal hexane, concentrated getting final product;
2-bromothiophene, n-Butyl Lithium, AlMe
2The mol ratio of Cl is 1:1:1.
7. the preparation method of a class aromatic base substituted thiophene according to claim 1 is characterized in that:
The structure of the 3-aromatic base of described aromatic base substituted thiophene (or assorted aromatic base) substituted thiophene compound or 2-aromatic base (or assorted aromatic base) substituted thiophene compound is as follows:
In the formula, R
1Be aromatic base, substituted aromatic base, assorted aromatic base.
8. the preparation method of a class aromatic base substituted thiophene according to claim 7 is characterized in that:
Described substituted aromatic base substituting group is methyl, methoxyl group, nitro or itrile group; Substituting group is 2-, 3-or 4-position.
9. the preparation method of a class aromatic base substituted thiophene according to claim 7 is characterized in that:
Described assorted aromatic base is 2-pyrimidine, 4-pyrimidine, 2-thiazole or 3-quinoline.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN110054611A (en) * | 2019-05-30 | 2019-07-26 | 广东工业大学 | A kind of biaryl ring derivatives and preparation method thereof that cyano replaces |
Citations (1)
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| CN1610712A (en) * | 2001-12-06 | 2005-04-27 | 科文有机半导体有限公司 | Process for producing aryl-aryl coupled compounds |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN1610712A (en) * | 2001-12-06 | 2005-04-27 | 科文有机半导体有限公司 | Process for producing aryl-aryl coupled compounds |
Non-Patent Citations (4)
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| ESTIBALIZ MERINO，ET AL.，: "Stereocontrolled Approach to Phenyl Cyclitols from (SR)-[(p-Tolylsulfinyl)methyl]-p-quinol", 《J. ORG. CHEM.》, vol. 74, no. 7, 24 February 2009 (2009-02-24), pages 2824 - 2831 * |
| KELVIN BILLINGSLEY，ET AL.，: "Highly Efficient Monophosphine-Based Catalyst for the Palladium-Catalyzed Suzuki-Miyaura Reaction of Heteroaryl Halides and Heteroaryl Boronic Acids and Esters", 《J.AM.CHEM.SOC.》, vol. 129, no. 11, 28 February 2007 (2007-02-28), pages 3358 - 3366, XP055056735, DOI: doi:10.1021/ja068577p * |
| WANG-TING SHU，ET AL.，: "Palladium-Catalyzed Cross-Coupling Reaction of AlArEt2(THF) with Aryl Bromides", 《SYNTHESIS》, no. 23, 10 December 2009 (2009-12-10), pages 4075 - 4081 * |
| 荣国斌: "《高等有机化学基础（第三版）》", 31 May 2009, article "1", pages: 233-234 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110054611A (en) * | 2019-05-30 | 2019-07-26 | 广东工业大学 | A kind of biaryl ring derivatives and preparation method thereof that cyano replaces |
| CN110054611B (en) * | 2019-05-30 | 2021-11-26 | 广东工业大学 | Cyano-substituted biaryl ring derivative and preparation method thereof |
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