CN103497083B - A kind of method preparing alkyl-substituted aromatic hydrocarbon - Google Patents
A kind of method preparing alkyl-substituted aromatic hydrocarbon Download PDFInfo
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Abstract
The invention discloses a kind of method preparing alkyl-substituted aromatic hydrocarbon, being specially with molecular formula is Fe (PPh
3)
2cl
3iron (III) title complex be single-component catalyst, under MAGNESIUM METAL exists, by halogenated aryl hydrocarbon and the cross-coupling reaction synthesis of alkyl substituted arene of primary, secondary halogenated alkyl hydrocarbon containing β-H.Preparation method's reaction conditions disclosed by the invention is gentle, can avoid using responsive Grignard reagent and many component catalyst systems, has very high catalytic activity, carry out simple column chromatography and just can obtain final product after having reacted alkyl hydrobromic ether and alkyl hydrochloric ether; And react raw materials used wide material sources, meet requirement and the direction of contemporary green chemistry, possess industrial application value.
Description
Technical field
The invention belongs to the preparing technical field of organic compound, be specifically related to a kind of catalysis preparation method of alkyl-substituted aromatic hydrocarbon.
Background technology
Alkyl-substituted aromatic hydrocarbon can be used as intermediate prepared by polymkeric substance and medicine.Such as by corresponding alkyl-substituted aromatic hydrocarbon peroxidation, then obtain corresponding phenol products through acidolysis, separation.This route compared with traditional aldehydes matter synthesis technique, have low stain, atom utilization high, be convenient to the advantages such as continuous prodution, be desirable green syt route.
The cross-coupling reaction of transition metal complex catalysis, as Kumada cross-coupling reaction, is one of most important method forming C-C, has become the class classics reaction in organic synthesis.Along with the intensification that people are familiar with chemical industry Sustainable development, Fe-series catalyst is considered to the Critical policies developing green high-efficient catalyzer because having the features such as cheapness, low toxicity, environmental friendliness.Wherein, develop Fe-series catalyst that is simple and easy to get, air-stable and receive very large concern in recent years.
At present, the method that traditional Kumada cross-coupling reaction prepares alkyl-substituted aromatic hydrocarbon adopts Fe-series catalyst, with aryl grignard reagent and containing β-H primary, secondary halogenated alkyl hydrocarbon for reaction substrate or with halogenated aryl hydrocarbon or vinyl halohydrocarbon and alkyl Grignard reagent for reaction substrate, reacted in organic solvent.This need to use tool dangerous, responsive and the Grignard reagent not easily prepared, and whole reaction process needs to take strict safety control measures, and this is have significant limitation to suitability for industrialized production.So need the cross-coupling reaction of development safety in order to prepare alkyl-substituted aromatic hydrocarbon.
2009; the people such as Jacobi von Wangelin report is using Anhydrous Ferric Chloride and Tetramethyl Ethylene Diamine (TMEDA) as catalyst system; the cross-coupling reaction of aryl halide and the primary, secondary halogenated alkyl hydrocarbon containing β-H is achieved first under MAGNESIUM METAL exists; prepare product alkyl-substituted aromatic hydrocarbon (see Czaplik, W. M.; Mayer, M.; Jacobi von Wangelin, A. Angew. Chem. Int. Ed., 2009,48,607).This reaction, by generating Grignard reagent at reaction process situ, successfully avoiding the direct use of Grignard reagent, is improve greatly one of traditional Kumada cross-coupling reaction, but, above-mentioned report also exists obvious drawback, mainly comprise: (1) Anhydrous Ferric Chloride very easily deliquescence, operation inconvenience, and the purity of Anhydrous Ferric Chloride is often mixed with other metal (as copper) of denier by its commercial source difference, thus cause the instability of catalytic performance, (2) need to use excessive containing n-donor ligand, rate of feeding is too slow, (3) reaction substrate primary limitation is containing primary of β-H, secondary alkyl hydrobromic ether, with alkyl bromide for hydrocarbon phase ratio, alkyl hydrochloric ether has obvious price advantage and diversity, have more commercial application prospect, but, the catalytic activity of iron catalyst to the cross-coupling reaction that the alkyl hydrochloric ether containing β-H participates in of above-mentioned exploitation need to improve, easily there is the side reactions such as dehalogenation in alkyl hydrochloric ether in coupling reaction process, the yield of target product is generally on the low side.
Therefore find that a kind of raw material sources are simple, reaction process is stablized, preparation method easy and simple to handle is necessary with efficient synthesis of alkyl substituted arene, the method also needs the cross-coupling reaction to alkyl hydrochloric ether participates in also to have higher catalytic activity simultaneously.
Summary of the invention
The object of this invention is to provide that a kind of raw material sources are simple, reaction process is stablized, preparation method easy and simple to handle, with simple, safety, prepare alkyl-substituted aromatic hydrocarbon efficiently.
To achieve the above object of the invention, the technical solution used in the present invention is:
Prepare a method for alkyl-substituted aromatic hydrocarbon, comprise the following steps:
(1) under anhydrous and oxygen-free condition, in inert atmosphere or nitrogen atmosphere, successively catalyzer, MAGNESIUM METAL and solvents tetrahydrofurane are added in reactor, stir 15 ~ 30 minutes in 0 ~ 30 DEG C; The molecular formula of described catalyzer is Fe (PPh
3)
2cl
3, expressed by the following chemical structure formula:
(2) in reactor, halogenated aryl hydrocarbon is added again and containing the primary, secondary halogenated alkyl hydrocarbon of β-H, prior to-10 ~ 10 DEG C of reactions 1 ~ 3 hour; Then in 0 ~ 40 DEG C of reaction 0 ~ 4 hour, by the aqueous solution termination reaction of saturated ammonium chloride; The described primary, secondary halogenated alkyl hydrocarbon containing β-H is the primary, secondary alkyl hydrobromic ether containing β-H or the primary, secondary alkyl hydrochloric ether containing β-H;
(3) reaction product is extracted with ethyl acetate, separating-purifying, obtains described alkyl-substituted aromatic hydrocarbon.
In technique scheme, described inert atmosphere is argon gas atmosphere.
In preferred technical scheme, the described primary, secondary halogenated alkyl hydrocarbon containing β-H is the primary, secondary alkyl hydrobromic ether containing β-H, in amount of substance, consumption containing the primary, secondary alkyl hydrobromic ether of β-H is 1.2 times of halogenated aryl hydrocarbon, the consumption of MAGNESIUM METAL is 1.2 times of halogenated aryl hydrocarbon, and the consumption of catalyzer is 5 % of halogenated aryl hydrocarbon; In step (2), the reaction times is 3 hours, and temperature is 0 DEG C.
In preferred technical scheme, the described primary, secondary halogenated alkyl hydrocarbon containing β-H is the primary, secondary alkyl hydrochloric ether containing β-H, in amount of substance, the consumption of halogenated aryl hydrocarbon is 1.2 times of the primary, secondary alkyl hydrochloric ether containing β-H, the consumption of MAGNESIUM METAL is 1.2 times of the primary, secondary alkyl hydrochloric ether containing β-H, and catalyst levels is 5% of the primary, secondary alkyl hydrochloric ether containing β-H; In step (2), prior to 0 DEG C of reaction 1 hour; Then in 20 DEG C of reactions 3 hours.
Further in preferred technical scheme, in step (1), churning time is 20 minutes, and temperature is room temperature.
In technique scheme, product is purified by column chromatography for separation.
In technique scheme, described MAGNESIUM METAL is magnesium chips.
In the present invention, catalyzer is iron (III) title complex, and molecular formula is Fe (PPh
3)
2cl
3(PPh
3for triphenylphosphine), its synthetic method is that prior art is (see Walker, J. D.; Poli, R. Inorg. Chem.1989,28,1793).
Principle of the present invention is: in two reaction substrates (i.e. halogenated aryl hydrocarbon and the primary, secondary halogenated alkyl hydrocarbon containing β-H), an active relatively high meeting reacts in-situ preparation Grignard reagent with MAGNESIUM METAL, the latter reacts with catalyzer iron (III) title complex the iron magnesium compound generating lower valency immediately, this mixture both can the generation of the follow-up Grignard reagent of catalysis, again can the Grignard reagent that generates of catalysis and in situ and relatively low another halohydrocarbon generation cross-coupling reaction of activity, thus generate target product alkyl-substituted aromatic hydrocarbon.
Carry out purification processes after the present invention has reacted, belong to prior art, those skilled in the art can select suitable reagent according to the character of final product.The present invention is preferably: reacted rear and first reacted with the aqueous solution cancellation of saturated ammonium chloride, be then extracted with ethyl acetate, then uses the mixed solvent of ethyl acetate/petroleum ether (volume ratio is 1: 100 ~ 20) to carry out simple column chromatography just can to obtain final product.
Because technique scheme is used, the present invention compared with prior art has following advantages:
1. iron of the present invention (III) composition catalyst has synthesis feature simple, stable in the air, is conducive to synthesizing use on a large scale; And there is clear and definite structure, the interference that other metal (as copper) avoiding denier may bring, it also avoid the use of Extra part;
2. the present invention adopts iron (III) title complex as catalyzer first, under the existence of MAGNESIUM METAL, catalysis halogenated aryl hydrocarbon and obtain alkyl-substituted aromatic hydrocarbon containing the cross-coupling reaction of primary, secondary halogenated alkyl hydrocarbon of β-H, reaction conditions is gentle, and product yield is high;
3. preparation method disclosed by the invention has universality to multiple reaction substrate, not only to halogenated aryl hydrocarbon with containing the cross-coupling reaction of the primary, secondary alkyl hydrobromic ether of β-H, there is high catalytic activity, equal or higher with the most high catalytic activity of iron trichloride system report at present, and can the halogenated aryl hydrocarbon of catalysis efficiently and contain the cross-coupling reaction of primary, secondary alkyl hydrochloric ether of β-H; And raw material sources are relatively easy, cost is low, easy and simple to handle, are conducive to the suitability for industrialized production of alkyl-substituted aromatic hydrocarbon.
Embodiment
Below in conjunction with embodiment to and comparative example the present invention be further described:
Embodiment one Fe (PPh
3)
2cl
3the cross-coupling reaction of catalysis para-bromo toluene and chlorocyclohexane
Under anhydrous and oxygen-free condition, in argon gas atmosphere, successively by 0.0343 gram of Fe (PPh
3)
2cl
3(0.05 mmole), the magnesium chips (1.2 mmole) of 0.0288 gram, 3 milliliters of tetrahydrofuran (THF)s are added in reaction flask, stir 20 minutes at ambient temperature.Add the para-bromo toluene (1.2 mmole) of 148 microlitres and the chlorocyclohexane (1.0 mmole) of 119 microlitres subsequently successively, 0 DEG C reaction 1 hour, after 20 DEG C reaction 3 hours.By the aqueous solution termination reaction of saturated ammonium chloride, reaction product is extracted with ethyl acetate, and column chromatography is purified (be that the mixed solvent of 1: 100 for developping agent with ethyl acetate/petroleum ether volume ratio), and productive rate is 92%.
Coupled product is dissolved in CDCl
3in (about 0.4 milliliter), tube sealing, under room temperature on Unity Inova-400 type NMR instrument measure characterize.
1H NMR (400 MHz, CDCl
3, TMS):1.28-1. 47 (5H, m), 1.74-1.88 (5H, m), 2.31 (3H, s), 2.46 (1H, m), 7.14 (4H, m)。
Embodiment two Fe (PPh
3)
2cl
3the cross-coupling reaction of catalysis para-bromo toluene and Sec-Butyl Chloride
Under anhydrous and oxygen-free condition, in nitrogen atmosphere, successively by 0.0343 gram of Fe (PPh
3)
2cl
3(0.05 mmole), the magnesium chips (1.2 mmole) of 0.0288 gram, 3 milliliters of tetrahydrofuran (THF)s are added in reaction flask, stir 20 minutes at ambient temperature.Add the para-bromo toluene (1.2 mmole) of 148 microlitres and the Sec-Butyl Chloride (1.0 mmole) of 107 microlitres subsequently successively, 0 DEG C reaction 1 hour, after 20 DEG C reaction 3 hours.By the aqueous solution termination reaction of saturated ammonium chloride, reaction product is extracted with ethyl acetate, and column chromatography is purified (be that the mixed solvent of 1: 100 for developping agent with ethyl acetate/petroleum ether volume ratio), and productive rate is 84%.
Coupled product is dissolved in CDCl
3in (about 0.4 milliliter), tube sealing, under room temperature on Unity Inova-400 type NMR instrument measure characterize.
1H NMR (400 MHz, CDCl
3, TMS):0.81 (3H, t), 1.21 (3H, d), 1.56 (2H, m), 2.32 (3H, s), 2.56 (1H, m), 7.00 (4H, m)。
Embodiment three Fe (PPh
3)
2cl
3the cross-coupling reaction of catalysis para-bromo toluene and 1-chloro-octane
Under anhydrous and oxygen-free condition, in argon gas atmosphere, successively by 0.0343 gram of Fe (PPh
3)
2cl
3(0.05 mmole), the magnesium chips (1.2 mmole) of 0.0288 gram, 3 milliliters of tetrahydrofuran (THF)s are added in reaction flask, stir 20 minutes at ambient temperature.Add the para-bromo toluene (1.2 mmole) of 148 microlitres and the 1-chloro-octane (1.0 mmole) of 170 microlitres subsequently successively, 0 DEG C reaction 1 hour, after 30 DEG C reaction 3 hours.By the aqueous solution termination reaction of saturated ammonium chloride, reaction product is extracted with ethyl acetate, and column chromatography is purified (be that the mixed solvent of 1: 100 for developping agent with ethyl acetate/petroleum ether volume ratio), and productive rate is 65%.
Coupled product is dissolved in CDCl
3in (about 0.4 milliliter), tube sealing, under room temperature on Unity Inova-400 type NMR instrument measure characterize.
1H NMR (400 MHz, CDCl
3, TMS):0.88 (3H, t), 1.27 (10H, m), 1.56 (2H, m), 2.31 (3H, s), 2.56 (2H, t), 7.17 (4H, m)。
Embodiment four Fe (PPh
3)
2cl
3the cross-coupling reaction of catalysis para-bromo toluene and chloro suberane
Under anhydrous and oxygen-free condition, in argon gas atmosphere, successively by 0.0343 gram of Fe (PPh
3)
2cl
3(0.05 mmole), the magnesium chips (1.2 mmole) of 0.0288 gram, 3 milliliters of tetrahydrofuran (THF)s are added in reaction flask, stir 30 minutes at ambient temperature.Add the para-bromo toluene (1.2 mmole) of 148 microlitres and the chloro suberane (1.0 mmole) of 132 microlitres subsequently successively, 0 DEG C reaction 1 hour, after 20 DEG C reaction 3 hours.By the aqueous solution termination reaction of saturated ammonium chloride, reaction product is extracted with ethyl acetate, and column chromatography is purified (be that the mixed solvent of 1: 100 for developping agent with ethyl acetate/petroleum ether volume ratio), and productive rate is 88%.
Coupled product is dissolved in CDCl
3in (about 0.4 milliliter), tube sealing, under room temperature on Unity Inova-400 type NMR instrument measure characterize.
1H NMR (400 MHz, CDCl
3, TMS):1.45-1.95 (12H, m), 2.30 (3H, s), 2.61 (1H, m), 7.17 (4H, m)。
Embodiment five Fe (PPh
3)
2cl
3the cross-coupling reaction of catalysis para-bromo toluene and chlorocyclopentane
Under anhydrous and oxygen-free condition, in argon gas atmosphere, successively by 0.0343 gram of Fe (PPh
3)
2cl
3(0.05 mmole), the magnesium chips (1.2 mmole) of 0.0288 gram, 3 milliliters of tetrahydrofuran (THF)s are added in reaction flask, stir 20 minutes under 10 DEG C of conditions.Add the para-bromo toluene (1.2 mmole) of 148 microlitres and the chlorocyclopentane (1.0 mmole) of 105 microlitres subsequently successively, 0 DEG C reaction 2 hours, after 20 DEG C reaction 2 hours.By the aqueous solution termination reaction of saturated ammonium chloride, reaction product is extracted with ethyl acetate, and column chromatography is purified (be that the mixed solvent of 1: 80 for developping agent with ethyl acetate/petroleum ether volume ratio), and productive rate is 70%.
Coupled product is dissolved in CDCl
3in (about 0.4 milliliter), tube sealing, under room temperature on Unity Inova-400 type NMR instrument measure characterize.
1H NMR (400 MHz, CDCl
3, TMS):1.50-1.73 (8H, m), 2.32 (3H, s), 2.95 (1H, m), 7.11 (4H, m)。
Embodiment six Fe (PPh
3)
2cl
3the cross-coupling reaction of catalysis 4-bromoanisole and chlorocyclohexane
Under anhydrous and oxygen-free condition, in argon gas atmosphere, successively by 0.0343 gram of Fe (PPh
3)
2cl
3(0.05 mmole), the magnesium chips (1.2 mmole) of 0.0288 gram, 3 milliliters of tetrahydrofuran (THF)s are added in reaction flask, stir 15 minutes at ambient temperature.Add the 4-bromoanisole (1.2 mmole) of 150 microlitres and the chlorocyclohexane (1.0 mmole) of 119 microlitres subsequently successively, 10 DEG C reaction 1 hour, after 30 DEG C reaction 3 hours.By the aqueous solution termination reaction of saturated ammonium chloride, reaction product is extracted with ethyl acetate, and column chromatography is purified (be that the mixed solvent of 1: 50 for developping agent with ethyl acetate/petroleum ether volume ratio), and productive rate is 86%.
Coupled product is dissolved in CDCl
3in (about 0.4 milliliter), tube sealing, under room temperature on Unity Inova-400 type NMR instrument measure characterize.
1H NMR (400 MHz, CDCl
3, TMS):1.28-1.47 (5H, m), 1.74-1.88 (5H, m), 2.44 (1H, m), 3.78 (3H, s), 7.00 (4H, m)。
Embodiment seven Fe (PPh
3)
2cl
3the cross-coupling reaction of catalysis 4-bromoanisole and Sec-Butyl Chloride
Under anhydrous and oxygen-free condition, in argon gas atmosphere, successively by 0.0343 gram of Fe (PPh
3)
2cl
3(0.05 mmole), the magnesium chips (1.2 mmole) of 0.0288 gram, 3 milliliters of tetrahydrofuran (THF)s are added in reaction flask, stir 20 minutes at ambient temperature.Add the 4-bromoanisole (1.2 mmole) of 150 microlitres and the Sec-Butyl Chloride (1.0 mmole) of 107 microlitres subsequently successively, 10 DEG C reaction 1 hour, after 40 DEG C reaction 3 hours.By the aqueous solution termination reaction of saturated ammonium chloride, reaction product is extracted with ethyl acetate, and column chromatography is purified (be that the mixed solvent of 1: 50 for developping agent with ethyl acetate/petroleum ether volume ratio), and productive rate is 54%.
Coupled product is dissolved in CDCl
3in (about 0.4 milliliter), tube sealing, under room temperature on Unity Inova-400 type NMR instrument measure characterize.
1H NMR (400 MHz, CDCl
3, TMS):0.80 (3H, t), 1.21 (3H, d), 1.56 (2H, m), 2.54 (1H, m), 3.82 (3H, s), 7.00 (4H, m)。
Embodiment eight Fe (PPh
3)
2cl
3the cross-coupling reaction of catalysis 4-bromoanisole and 1-chloro-octane
Under anhydrous and oxygen-free condition, in argon gas atmosphere, successively by 0.0343 gram of Fe (PPh
3)
2cl
3(0.05 mmole), the magnesium chips (1.2 mmole) of 0.0288 gram, 3 milliliters of tetrahydrofuran (THF)s are added in reaction flask, stir 20 minutes at ambient temperature.Add the 4-bromoanisole (1.2 mmole) of 150 microlitres and the 1-chloro-octane (1.0 mmole) of 170 microlitres subsequently successively, 0 DEG C reaction 1 hour, after 10 DEG C reaction 3 hours.By the aqueous solution termination reaction of saturated ammonium chloride, reaction product is extracted with ethyl acetate, and column chromatography is purified (be that the mixed solvent of 1: 50 for developping agent with ethyl acetate/petroleum ether volume ratio), and productive rate is 43%.
Coupled product is dissolved in CDCl
3in (about 0.4 milliliter), tube sealing, under room temperature on Unity Inova-400 type NMR instrument measure characterize.
1H NMR (400 MHz, CDCl
3, TMS):0.87 (3H, t), 1.27 (10H, m), 1.56 (2H, m), 2.56 (2H, t), 3.82 (3H, s), 7.00 (4H, m)。
Embodiment nine Fe (PPh
3)
2cl
3the cross-coupling reaction of catalysis 2 bromo toluene and chlorocyclohexane
Under anhydrous and oxygen-free condition, in argon gas atmosphere, successively by 0.0343 gram of Fe (PPh
3)
2cl
3(0.05 mmole), the magnesium chips (1.2 mmole) of 0.0288 gram, 3 milliliters of tetrahydrofuran (THF)s are added in reaction flask, stir 20 minutes at ambient temperature.Add the 2 bromo toluene (1.2 mmole) of 144 microlitres and the chlorocyclohexane (1.0 mmole) of 119 microlitres subsequently successively, 0 DEG C reaction 1 hour, after 20 DEG C reaction 3 hours.By the aqueous solution termination reaction of saturated ammonium chloride, reaction product is extracted with ethyl acetate, and column chromatography is purified (be that the mixed solvent of 1: 100 for developping agent with ethyl acetate/petroleum ether volume ratio), and productive rate is 93%.
Coupled product is dissolved in CDCl
3in (about 0.4 milliliter), tube sealing, under room temperature on Unity Inova-400 type NMR instrument measure characterize.
1H NMR (400 MHz, CDCl
3, TMS):1.20-1. 47 (5H, m), 1.74-1.88 (5H, m), 2.33 (3H, s), 2.92 (1H, m), 7.14 (4H, m)。
Embodiment ten Fe (PPh
3)
2cl
3the 1-bromonaphthalene of catalysis and the cross-coupling reaction of chlorocyclohexane
Under anhydrous and oxygen-free condition, in argon gas atmosphere, successively by 0.0343 gram of Fe (PPh
3)
2cl
3(0.05 mmole), the magnesium chips (1.2 mmole) of 0.0288 gram, 3 milliliters of tetrahydrofuran (THF)s are added in reaction flask, stir 20 minutes at ambient temperature.Add the 1-bromonaphthalene (1.2 mmole) of 168 microlitres and the chlorocyclohexane (1.0 mmole) of 119 microlitres subsequently successively, 0 DEG C reaction 1 hour, after 40 DEG C reaction 3 hours.By the aqueous solution termination reaction of saturated ammonium chloride, reaction product is extracted with ethyl acetate, and column chromatography is purified (be that the mixed solvent of 1: 100 for developping agent with ethyl acetate/petroleum ether volume ratio), and productive rate is 80%.
Coupled product is dissolved in CDCl
3in (about 0.4 milliliter), tube sealing, under room temperature on Unity Inova-400 type NMR instrument measure characterize.
1H NMR (400 MHz, CDCl
3, TMS):1.26-1.70 (5H, m), 1.79-2.19 (5H, m), 3.42 (1H, m), 7.54 (4H, m), 7.75 (1H, d), 7.92 (1H, m), 8.11 (1H, d)。
Embodiment 11 Fe (PPh
3)
2cl
3the cross-coupling reaction of catalysis 2-methyl-2-(4-bromophenyl)-DOX and chlorocyclohexane
Under anhydrous and oxygen-free condition, in argon gas atmosphere, successively by 0.0343 gram of Fe (PPh
3)
2cl
3(0.05 mmole), the magnesium chips (1.2 mmole) of 0.0288 gram, 3 milliliters of tetrahydrofuran (THF)s are added in reaction flask, stir 20 minutes at ambient temperature.Add 2-methyl-2-(4-the bromophenyl)-DOX (1.2 mmole) of 200 microlitres and the chlorocyclohexane (1.0 mmole) of 119 microlitres subsequently successively, 0 DEG C reaction 1 hour, after 20 DEG C reaction 3 hours.By the aqueous solution termination reaction of saturated ammonium chloride, reaction product is extracted with ethyl acetate, and column chromatography is purified (be that the mixed solvent of 1: 20 for developping agent with ethyl acetate/petroleum ether volume ratio), and productive rate is 82%.
Coupled product is dissolved in CDCl
3in (about 0.4 milliliter), tube sealing, under room temperature on Unity Inova-400 type NMR instrument measure characterize.
1H NMR (400 MHz, CDCl
3, TMS):1.28-1.47 (5H, m), 1.61(3H, s), 1.75-1.88 (5H, m), 2.42 (1H, m), 3.72(2H, t), 3.96 (2H, t), 7.20 (4H, m)。
Embodiment 12 Fe (PPh
3)
2cl
3the linked reaction of catalysis 2-bromopyridine and chlorocyclohexane
Under anhydrous and oxygen-free condition, in argon gas atmosphere, successively by 0.0343 gram of Fe (PPh
3)
2cl
3(0.05 mmole), the magnesium chips (1.2 mmole) of 0.0288 gram, 3 milliliters of tetrahydrofuran (THF)s are added in reaction flask, stir 20 minutes at ambient temperature.Add the 2-bromopyridine (1.2 mmole) of 114 microlitres and the chlorocyclohexane (1.0 mmole) of 119 microlitres subsequently successively, 0 DEG C reaction 1 hour, after 20 DEG C reaction 3 hours.By the aqueous solution termination reaction of saturated ammonium chloride, reaction product is extracted with ethyl acetate, and column chromatography is purified (be that the mixed solvent of 1: 100 for developping agent with ethyl acetate/petroleum ether volume ratio), and productive rate is 70%.
Coupled product is dissolved in CDCl
3in (about 0.4 milliliter), tube sealing, under room temperature on Unity Inova-400 type NMR instrument measure characterize.
1H NMR (400 MHz, CDCl
3, TMS):1.25-1. 47 (5H, m), 1.74-1.96 (5H, m), 2.69 (1H, m), 7.10 (2H, m), 7.59 (1H, m), 8.51 (1H, d)。
Embodiment 13 Fe (PPh
3)
2cl
3the linked reaction of catalysis 2-chloropyridine and chlorocyclohexane
Under anhydrous and oxygen-free condition, in argon gas atmosphere, successively by 0.0343 gram of Fe (PPh
3)
2cl
3(0.05 mmole), the magnesium chips (1.2 mmole) of 0.0288 gram, 3 milliliters of tetrahydrofuran (THF)s are added in reaction flask, stir 20 minutes under 0 DEG C of condition.Add the 2-chloropyridine (1.2 mmole) of 113 microlitres and the chlorocyclohexane (1.0 mmole) of 119 microlitres subsequently successively, 0 DEG C reaction 1 hour, after 30 DEG C reaction 3 hours.By the aqueous solution termination reaction of saturated ammonium chloride, reaction product is extracted with ethyl acetate, and column chromatography is purified (be that the mixed solvent of 1: 100 for developping agent with ethyl acetate/petroleum ether volume ratio), and productive rate is 40%.
Coupled product is dissolved in CDCl
3in (about 0.4 milliliter), tube sealing, under room temperature on Unity Inova-400 type NMR instrument measure characterize.
1H NMR (400 MHz, CDCl
3, TMS):1.25-1. 47 (5H, m), 1.74-1.96 (5H, m), 2.69 (1H, m), 7.10 (2H, m), 7.59 (1H,m), 8.51 (1H, d)。
Embodiment 14 Fe (PPh
3)
2cl
3the cross-coupling reaction of catalysis para-bromo toluene and bromocyclohexane
Under anhydrous and oxygen-free condition, in argon gas atmosphere, successively by 0.0343 gram of Fe (PPh
3)
2cl
3(0.05 mmole), the magnesium chips (1.2 mmole) of 0.0288 gram, 3 milliliters of tetrahydrofuran (THF)s are added in reaction flask, stir 20 minutes at ambient temperature.Add the para-bromo toluene (1.0 mmole) of 123 microlitres and the bromocyclohexane (1.2 mmole) of 148 microlitres subsequently successively, 0 DEG C of reaction 3 hours.By the aqueous solution termination reaction of saturated ammonium chloride, reaction product is extracted with ethyl acetate, and column chromatography is purified (be that the mixed solvent of 1: 100 for developping agent with ethyl acetate/petroleum ether volume ratio), and productive rate is 94%.
Coupled product is dissolved in CDCl
3in (about 0.4 milliliter), tube sealing, under room temperature on Unity Inova-400 type NMR instrument measure characterize.
1H NMR (400 MHz, CDCl
3, TMS):1.28-1. 47 (5H, m), 1.74-1.88 (5H, m), 2.35 (3H, s), 2.50 (1H, m), 7.14 (4H, m)。
Embodiment 15 Fe (PPh
3)
2cl
3the cross-coupling reaction of catalysis para-bromo toluene and 2-n-butyl bromide
Under anhydrous and oxygen-free condition, in argon gas atmosphere, successively by 0.0343 gram of Fe (PPh
3)
2cl
3(0.05 mmole), the magnesium chips (1.2 mmole) of 0.0288 gram, 3 milliliters of tetrahydrofuran (THF)s are added in reaction flask, stir 20 minutes at ambient temperature.Add the para-bromo toluene (1.0 mmole) of 123 microlitres and the 2-n-butyl bromide (1.2 mmole) of 131 microlitres subsequently successively, 0 DEG C of reaction 3 hours.By the aqueous solution termination reaction of saturated ammonium chloride, reaction product is extracted with ethyl acetate, and column chromatography is purified (be that the mixed solvent of 1: 100 for developping agent with ethyl acetate/petroleum ether volume ratio), and productive rate is 86%.
Coupled product is dissolved in CDCl
3in (about 0.4 milliliter), tube sealing, under room temperature on Unity Inova-400 type NMR instrument measure characterize.
1H NMR (400 MHz, CDCl
3, TMS):0.81 (3H, t), 1.22 (3H, d), 1.56 (2H, m), 2.32 (3H, s), 2.56 (1H, m), 7.02 (4H, m)。
Embodiment 16 Fe (PPh
3)
2cl
3the cross-coupling reaction of catalysis para-bromo toluene and 1-bromooctane
Under anhydrous and oxygen-free condition, in argon gas atmosphere, successively by 0.0343 gram of Fe (PPh
3)
2cl
3(0.05 mmole), the magnesium chips (1.2 mmole) of 0.0288 gram, 3 milliliters of tetrahydrofuran (THF)s are added in reaction flask, stir 30 minutes under 10 DEG C of conditions.Add the para-bromo toluene (1.0 mmole) of 123 microlitres and the 1-bromooctane (1.2 mmole) of 207 microlitres subsequently successively, 10 DEG C of reactions 3 hours.By the aqueous solution termination reaction of saturated ammonium chloride, reaction product is extracted with ethyl acetate, and column chromatography is purified (be that the mixed solvent of 1: 100 for developping agent with ethyl acetate/petroleum ether volume ratio), and productive rate is 70%.
Coupled product is dissolved in CDCl
3in (about 0.4 milliliter), tube sealing, under room temperature on Unity Inova-400 type NMR instrument measure characterize.
1H NMR (400 MHz, CDCl
3, TMS):0.89 (3H, t), 1.28 (10H, m), 1.56 (2H, m), 2.33 (3H, s), 2.56 (2H, t), 7.16 (4H, m)。
Embodiment 17 Fe (PPh
3)
2cl
3the cross-coupling reaction of catalysis 4-bromoanisole and 2-n-butyl bromide
Under anhydrous and oxygen-free condition, in argon gas atmosphere, successively by 0.0343 gram of Fe (PPh
3)
2cl
3(0.05 mmole), the magnesium chips (1.2 mmole) of 0.0288 gram, 3 milliliters of tetrahydrofuran (THF)s are added in reaction flask, stir 20 minutes at ambient temperature.Add the 4-bromoanisole (1.0 mmole) of 125 microlitres and the 2-n-butyl bromide (1.2 mmole) of 131 microlitres subsequently successively, 0 DEG C of reaction 3 hours.By the aqueous solution termination reaction of saturated ammonium chloride, reaction product is extracted with ethyl acetate, and column chromatography is purified (be that the mixed solvent of 1: 50 for developping agent with ethyl acetate/petroleum ether volume ratio), and productive rate is 84%.
Coupled product is dissolved in CDCl
3in (about 0.4 milliliter), tube sealing, under room temperature on Unity Inova-400 type NMR instrument measure characterize.
1H NMR (400 MHz, CDCl
3, TMS):0.81 (3H, t), 1.21 (3H, d), 1.57 (2H, m), 2.54 (1H, m), 3.82 (3H, s), 7.02 (4H, m)。
Embodiment 18 Fe (PPh
3)
2cl
3the 1-bromonaphthalene of catalysis and the cross-coupling reaction of bromocyclohexane
Under anhydrous and oxygen-free condition, in argon gas atmosphere, successively by 0.0343 gram of Fe (PPh
3)
2cl
3(0.05 mmole), the magnesium chips (1.2 mmole) of 0.0288 gram, 3 milliliters of tetrahydrofuran (THF)s are added in reaction flask, stir 20 minutes at ambient temperature.Add the 1-bromonaphthalene (1.0 mmole) of 148 microlitres and the bromocyclohexane (1.2 mmole) of 148 microlitres subsequently successively, 0 DEG C of reaction 3 hours.By the aqueous solution termination reaction of saturated ammonium chloride, reaction product is extracted with ethyl acetate, and column chromatography is purified (be that the mixed solvent of 1: 100 for developping agent with ethyl acetate/petroleum ether volume ratio), and productive rate is 88%.
Coupled product is dissolved in CDCl
3in (about 0.4 milliliter), tube sealing, under room temperature on Unity Inova-400 type NMR instrument measure characterize.
1H NMR (400 MHz, CDCl
3, TMS):1.26-1.70 (5H, m), 1.79-2.19 (5H, m), 3.42 (1H, m), 7.54 (4H, m), 7.75 (1H, d), 7.92 (1H, m), 8.11 (1H, d)。
Comparative example one FeCl
3the cross-coupling reaction of catalysis para-bromo toluene and chlorocyclohexane
Under anhydrous and oxygen-free condition, in argon gas atmosphere, successively by 0.0081 gram of FeCl
3(0.05 mmole), the magnesium chips (1.2 mmole) of 0.0288 gram, 3 milliliters of tetrahydrofuran (THF)s are added in reaction flask, stir 20 minutes at ambient temperature.Add the para-bromo toluene (1.2 mmole) of 148 microlitres and the chlorocyclohexane (1 mmole) of 119 microlitres subsequently successively, 0 DEG C reaction 1 hour, after 20 DEG C reaction 3 hours.By the aqueous solution termination reaction of saturated ammonium chloride, reaction product is extracted with ethyl acetate, and column chromatography is purified (be that the mixed solvent of 1: 100 for developping agent with ethyl acetate/petroleum ether volume ratio), and productive rate is 27%.
Coupled product is dissolved in CDCl
3in (about 0.4 milliliter), tube sealing, under room temperature on Unity Inova-400 type NMR instrument measure characterize.
1H NMR (400 MHz, CDCl
3, TMS):1.28-1. 47 (5H, m), 1.74-1.88 (5H, m), 2.31 (3H, s), 2.46 (1H, m), 7.14 (4H, m)。
Claims (8)
1. prepare a method for alkyl-substituted aromatic hydrocarbon, it is characterized in that, comprise the following steps:
(1) under anhydrous and oxygen-free condition, in inert atmosphere or nitrogen atmosphere, successively catalyzer, MAGNESIUM METAL and solvents tetrahydrofurane are added in reactor, stir 15 ~ 30 minutes in 0 ~ 30 DEG C; The molecular formula of described catalyzer is Fe (PPh
3)
2cl
3, expressed by the following chemical structure formula:
(2) in reactor, halogenated aryl hydrocarbon is added again and containing the primary, secondary halogenated alkyl hydrocarbon of β-H, prior to-10 ~ 10 DEG C of reactions 1 ~ 3 hour; Then in 0 ~ 40 DEG C of reaction 0 ~ 4 hour, by the aqueous solution termination reaction of saturated ammonium chloride; The described primary, secondary halogenated alkyl hydrocarbon containing β-H is the primary, secondary alkyl hydrobromic ether containing β-H or the primary, secondary alkyl hydrochloric ether containing β-H;
(3) reaction product is extracted with ethyl acetate, separating-purifying, obtains described alkyl-substituted aromatic hydrocarbon.
2. prepare the method for alkyl-substituted aromatic hydrocarbon according to claim 1, it is characterized in that: described inert atmosphere is argon gas atmosphere.
3. prepare the method for alkyl-substituted aromatic hydrocarbon according to claim 1, it is characterized in that: the described primary, secondary halogenated alkyl hydrocarbon containing β-H is alkyl hydrobromic ether, in amount of substance, consumption containing the primary, secondary alkyl hydrobromic ether of β-H is 1.2 times of halogenated aryl hydrocarbon, the consumption of MAGNESIUM METAL is 1.2 times of halogenated aryl hydrocarbon, and catalyst levels is 5 % of halogenated aryl hydrocarbon; In step (2), the reaction times is 3 hours, and temperature is 0 DEG C.
4. prepare the method for alkyl-substituted aromatic hydrocarbon according to claim 3, it is characterized in that: in step (1), churning time is 20 minutes, and temperature is room temperature.
5. prepare the method for alkyl-substituted aromatic hydrocarbon according to claim 1, it is characterized in that: the described primary, secondary halogenated alkyl hydrocarbon containing β-H is the primary, secondary alkyl hydrochloric ether containing β-H, in amount of substance, the consumption of halogenated aryl hydrocarbon is 1.2 times of the primary, secondary alkyl hydrochloric ether containing β-H, the consumption of MAGNESIUM METAL is 1.2 times of the primary, secondary alkyl hydrochloric ether containing β-H, and catalyst levels is 5 % of the primary, secondary alkyl hydrochloric ether containing β-H; In step (2), prior to 0 DEG C of reaction 1 hour; Then in 20 DEG C of reactions 3 hours.
6. prepare the method for alkyl-substituted aromatic hydrocarbon according to claim 5, it is characterized in that: in step (1), churning time is 20 minutes, and temperature is room temperature.
7. prepare the method for alkyl-substituted aromatic hydrocarbon according to claim 1, it is characterized in that: product is purified by column chromatography for separation.
8. prepare the method for alkyl-substituted aromatic hydrocarbon according to claim 1, it is characterized in that: described MAGNESIUM METAL is magnesium chips.
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| Title |
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| Domino Iron Catalysis: Direct Aryl–Alkyl Cross-Coupling;Waldemar Maximilian Czaplik et al.;《Angew. Chem. Int. Ed.》;20081209;第48卷;第607–610页，Supporting Information * |
| Iron Phosphine, Phosphite, Arsine, and Carbene Catalysts for the Coupling of Primary and Secondary Alkyl Halides with Aryl;Robin B. Bedford et al.;《J. Org. Chem.》;20051224;第71卷(第3期);第1104-1110页 * |
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