CN108689923B - Novel green and practical synthesis method of N, N-dimethylpyridine compound - Google Patents
Novel green and practical synthesis method of N, N-dimethylpyridine compound Download PDFInfo
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- CN108689923B CN108689923B CN201810756777.9A CN201810756777A CN108689923B CN 108689923 B CN108689923 B CN 108689923B CN 201810756777 A CN201810756777 A CN 201810756777A CN 108689923 B CN108689923 B CN 108689923B
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/72—Nitrogen atoms
- C07D213/74—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
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Abstract
The invention relates to a novel green and practical method for synthesizing an N, N-dimethylpyridine compound. The reaction method uses common inorganic base and water as an accelerant and a reaction solvent respectively, and can smoothly promote the 2-halogenated pyridine derivative and the N, N-dimethyl amide compound to selectively perform dehalogenation amination reaction in air under mild conditions to generate the corresponding N, N-dimethyl pyridine derivative. The method creatively realizes the direct amination reaction of the inorganic base promoted 2-halogenated pyridine compound and the N, N-disubstituted formamide compound which are cheap and easy to obtain for the first time, overcomes the limitation that the traditional method needs to use a metal catalyst, and provides a brand new strategy for preparing and industrially producing the N, N-dimethylpyridine compound in a laboratory.
Description
Technical Field
The invention relates to a novel green and practical method for synthesizing an N, N-dimethylpyridine compound.
Background
The N, N-dimethylpyridine skeleton is widely present in drug molecules, dyes and pesticide molecules, has great synthetic value and significance, and draws wide attention of scientific research workers. As early as 1979, large excesses of oxygen-containing inorganic bases, such as: KOH is also widely used in the amination research of 2-substituted pyridine derivatives (Synthesis 1980,39), however, DMF (N, N-dimethylformamide) and DMA (N, N-dimethylacetamide) are used as an amine source and a reaction solvent in the reaction, the reaction temperature needs 150-190 ℃ to obtain higher reaction yield, the atom economy of the reaction system is poor, and the reaction conditions are harsh. Two of the most common methods currently used are base-promoted methylation of aniline compounds (j.mol. catl. a: chem.2005,226,49), reductive amination of aniline and formaldehyde (tetrahedron lett.2007,48,7680). However, the system has poor product selectivity, and the application value of the reaction is influenced by the inevitable production of a single product and a double-substituted product in the product. In addition, the reaction also needs to use a methylating agent with high toxicity, so that the atom economy of the reaction is poor and the practical application value is high. In recent years, scientists have conducted extensive research on the amination of aryl halohydrocarbons with excellent results, such as: copper-catalyzed arylation of N, N-dimethylamine or N-methylamine (adv. synth. cat. 2015,357,714), zinc-promoted "amine source" and amino acid reduction methylation reaction, and the like, all of which have achieved some success, most of which involve excessive heavy metal reagents, harsh reaction conditions and some toxic solvents, and all of which deviate from the concept of green chemistry. Therefore, the development of an efficient and green synthetic method of the N, N-dimethylpyridine compound not only has important economic benefits, but also has good environmental and social benefits.
Compared with the traditional or expensive metal-catalyzed N, N-dimethylpyridine compound synthesis method with poor atom economy, the cheap and easily-obtained inorganic base catalysis method obviously has the advantages of convenience in operation, low production cost, high industrial application value and the like, but the method is very rare at home and abroad at present. In recent years, inorganic base catalytic systems have provided people with an important direction for environmentally friendly catalytic reactions, and have been successfully applied to catalytic reactions, such as: the biaryl (nat. chem.2010,2,1044) is constructed by activating the carbon-hydrogen bond of the arene and the halogenated hydrocarbon, and the method has the characteristics of simplicity and convenience in operation, environmental friendliness, low production cost and the like. Therefore, the development and utilization of an inorganic base system for promoting the synthesis of the N, N-dimethylpyridine compound has great industrial and laboratory application prospects.
Disclosure of Invention
The invention aims to replace the traditional or metal-catalyzed synthesis method of the N, N-dimethylpyridine compound, provide a reaction system which is efficient, environment-friendly, cheap and easily available, and realize the synthesis of the N, N-dimethylpyridine compound under a mild condition, so as to overcome the limitation that the traditional method needs to use toxic inorganic reagents or expensive metal catalysts to participate in the reaction, and provide a brand-new strategy for laboratory preparation and industrial production.
According to the invention, a new method for synthesizing a green and practical N, N-lutidine compound is characterized in that the method comprises the following steps of using cheap and easily available inorganic base such as: potassium (sodium) tert-butoxide and potassium (sodium) trimethylsilanolate are used as catalysts, N-dimethylamide compounds and water are used as reaction solvents, and the 2-halogenated pyridine derivatives and the N, N-dimethylamide compounds can be efficiently subjected to dehalogenation amination reaction selectively under mild reaction temperature, normal pressure and air environment to generate corresponding N, N-dimethylpyridine derivatives.
Wherein R in the 2-halogenated pyridine compound1Is a substituent at ortho, meta and para positions on the aryl, such as: alkyl, aryl, halogen, ester group, alkoxy, mercaptoalkyl, trifluoromethyl, cyano, alkenyl, amino, heterocycle, silicon group.
Wherein, the inorganic base catalyst is: potassium (sodium) tert-butoxide and potassium (sodium) trimethylsilanolate.
Wherein the amount of the inorganic base catalyst is 1-4 equivalents of the pyridine compound.
Wherein the reaction solvent is water.
Wherein the reaction conditions are normal pressure and air environment, and the reaction temperature is 25-160 ℃.
Wherein the reaction substrate is a 2-halogenated pyridine derivative or an N, N-dimethyl amide compound.
Wherein, the used reaction substrate and inorganic base catalyst are characterized in that the reaction substrate and the inorganic base catalyst are common commercial reagents, the purity is more than 95 percent, and the purification treatment is not needed; wherein the water is deionized water.
The process of the selective dehalogenation amination reaction of the 2-halogenated pyridine derivative and the N, N-dimethyl amide compound by the participation of the inorganic base is as follows:
in the air, the corresponding halogenated pyridine derivative, inorganic base and solvent are added into a reaction bottle in sequence to obtain white turbid liquid. And then, placing the reaction bottle at 25-160 ℃ for stirring reaction, tracking the reaction process according to TLC, and after the reaction is finished, adding an internal standard into the crude product to determine the yield of the product through GC and GC-MS, or directly separating the product through column chromatography to obtain the product and the yield.
Conditions for carrying out the method
The present invention will be further described with reference to specific examples, which are only used to illustrate the technical solutions of the present invention, but not to limit the present invention.
Example 1
2, 5-dibromopyridine (1mmol), DMF (1mmol), potassium (sodium) tert-butoxide or potassium (sodium) trimethylsilanolate (1mmol) as inorganic base and 2mL of water are sequentially added into a 10mL sealed tube, heated and stirred for 6 hours in an oil bath at 100 ℃, the reaction progress is tracked according to TLC, the reaction is finished, and the accurate yield of the product is determined by GC and GC-MS by adding the equivalent weight of o-dimethyl ether as an internal standard into the crude product. According to GC and GC-MS, when DMSO is used as a reaction solvent and potassium (sodium) tert-butoxide or potassium (sodium) trimethylsilanolate as a catalyst, the yields of the products are 42%, 59%, 67%, 60% in this order. Nuclear magnetic data of the product:1H NMR(400MHz,CDCl3):8.15(s,1H),7.47(d,J＝8Hz,1H),6.39(d,J＝8Hz,1H),3.04(s,6H).
example 2
Sequentially adding 2, 5-dibromopyridine (1.0mmol), DMF (1mmol), sodium tert-butoxide (0.5-4.0mmol) and 2mL of water into a 10mL sealed tube, heating in oil bath at 140 ℃, stirring for 6 hours, quenching with dichloromethane, after the reaction is finished, adding an internal standard into the crude product to determine the yield of the product by GC and GC-MS, and when the sodium tert-butoxide is 0.5mmol, 1.0mmol, 2.0mmol, 3.0mmol and 4.0mmol, the separation yields of the product are respectively 55%, 66%, 72%, 80% and 82%.
Example 3
Sequentially adding 2, 5-dibromopyridine (1.0mmol), DMF (1mmol), sodium tert-butoxide (3.0mmol) and 2mL of water into a 10mL sealed tube, heating and stirring in an oil bath at 25-140 ℃ for 6 hours, quenching with dichloromethane, adding an internal standard into the crude product after the reaction is finished, determining the yield of the product by GC and GC-MS, and when the temperature is 25 ℃, 80 ℃, 100 ℃ and 140 ℃, the separation yield of the product is 0%, 36%, 59% and 80% respectively.
Example 4
Sequentially adding 2, 5-dibromopyridine (1.0mmol), DMF (1mmol), inorganic base (3.0mmol) and 2mL of water into a 10mL sealed tube, heating and stirring in an oil bath at 140 ℃ for 6 hours, quenching with dichloromethane, after the reaction is finished, adding an internal standard into the crude product, and determining the yield of the product by GC and GC-MS, wherein when the inorganic base is potassium tert-butoxide, sodium tert-butoxide, potassium methoxide, potassium trimethylsilanolate and sodium trimethylsilanolate, the separation yields of the product are respectively 42%, 80%, 9%, 67% and 60%; when the base is monopotassium phosphate, potassium carbonate, sodium tetrafluoroborate, potassium fluoride, potassium acetate, sodium bicarbonate, sodium formate, triethylamine, DBU (1, 8-diazabicyclo [5.4.0] undec-7-ene), the target product is not detected in the reaction, and the yield is 0%.
Example 5
Sequentially adding 2, 5-dibromopyridine (1.0mmol), DMF (1mmol), sodium tert-butoxide (3.0mmol) and 2mL of solvent into a 10mL sealed tube, heating and stirring in an oil bath at 140 ℃ for 6 hours, quenching the reaction by using dichloromethane, adding an internal standard into the crude product after the reaction is finished, determining the yield of the product by GC and GC-MS, and when the solvent is DMSO, p-xylene, methanol, ethanol, water, DCM, THF and 1, 4-dioxane, respectively: 3%, 8%, 11%, 54%, 80%, 0%, 10%.
Example 6
Sequentially adding 2, 5-dibromopyridine (1.0mmol), DMF (1.0-10.0mmol), sodium tert-butoxide (3.0mmol) and 2mL of solvent into a 10mL sealed tube, heating and stirring in an oil bath at 140 ℃ for 6 hours, quenching with dichloromethane, after the reaction is finished, adding an internal standard into the crude product to determine the yield of the product by GC and GC-MS, wherein when the DMF is 1.0mmol, 2.0mmol, 3.0mmol, 4.0mmol, 6.0mmol and 10.0mmol, the product yields are respectively: 80%, 82%, 83%, 82%.
Example 7
Sequentially adding 2, 5-dibromopyridine (1.0mmol), DMF (2.0mmol), sodium tert-butoxide (3.0mmol) and 2mL of solvent into a 10mL sealed tube, heating and stirring at 140 ℃ in an oil bath for 0.5-24 hours, quenching with dichloromethane, adding an internal standard into the crude product after the reaction is finished, determining the yield of the product by GC and GC-MS, and determining the yield of the product by 27%, 57%, 66%, 80%, 87% and 92% when the reaction time is 0.5, 1 hour, 2 hours, 6 hours, 12 hours and 24 hours.
It should be noted that the above summary and the detailed description are intended to demonstrate the practical application of the technical solutions provided by the present invention, and should not be construed as limiting the scope of the present invention. Various modifications, equivalent substitutions, or improvements may be made by those skilled in the art within the spirit and principles of the invention. The scope of the invention is to be determined by the appended claims.
Claims (1)
1. A method for synthesizing an N, N-dimethylpyridine compound is characterized by comprising the following steps: sequentially adding 1.0mmol of 2, 5-dibromopyridine, 2.0mmol of DMF, 3.0mmol of sodium tert-butoxide and 2mL of water into a 10mL sealed tube, heating in an oil bath at 140 ℃ and stirring for 24 hours, quenching with dichloromethane, after the reaction is finished, adding an internal standard into the crude product, and determining the yield of the product by GC and GC-MS, wherein the product is 5-bromo-2-dimethylaminopyridine.
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Non-Patent Citations (3)
| Title |
|---|
| 4-Amino-5-aryl-6-arylethynylpyrimidines: Structure-activity relationships of non-nucleoside adenosine kinase inhibitors;Mark A. Matulenko等;《Bioorganic & Medicinal Chemistry》;20061220;第15卷(第4期);Supporting Infomation第S23页 * |
| A Very Convenient Dimethylamination of Activated Aromatic Halides Using N,N-Dimethylformamide and Ethanolamines;Yoon Hwan Cho等;《Tetrahedron Letters》;19971231;第38卷(第48期);8331-8334 * |
| General method for nucleophilic aromatic substitution of aryl fluorides and chlorides with dimethylamine using hydroxide-assisted decomposition of N,N-dimethylforamide;Juana Garcia等;《Synthetic Communications》;20161231;第46卷(第5期);第475、477-479页 * |
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