CN107089940B - A kind of 2-（3- alkyl phenoxies）The preparation method of pyridine derivate - Google Patents
A kind of 2-（3- alkyl phenoxies）The preparation method of pyridine derivate Download PDFInfo
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- CN107089940B CN107089940B CN201710292323.6A CN201710292323A CN107089940B CN 107089940 B CN107089940 B CN 107089940B CN 201710292323 A CN201710292323 A CN 201710292323A CN 107089940 B CN107089940 B CN 107089940B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- 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
- C07D213/62—Oxygen or sulfur atoms
- C07D213/63—One oxygen atom
- C07D213/64—One oxygen atom attached in position 2 or 6
- C07D213/643—2-Phenoxypyridines; Derivatives thereof
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B53/00—Asymmetric syntheses
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- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
Abstract
One kind 2（3 alkyl phenoxies）The preparation method of pyridine derivate reacts preparation using 2 phenoxypyridine derivatives with brominated methans compound, and reaction process is：2 phenoxypyridine derivatives, two or three-level brominated methans compound, catalyst, additive, alkali and solvent are directly added into reaction unit, the catalyst is bis- (the 4 isopropyl methyl phenyl) rutheniums of dichloro；Alkali is potassium carbonate or lithium carbonate, and the additive is 1 adamantane acid or naphthenic acid；The solvent is benzene or DMF or glycol dimethyl ether, and agitating and heating temperature is reacted 12 48 hours, separation product obtains 2 to 80 DEG C 140 DEG C（3 alkyl phenoxies）This reaction of pyridine derivate can be with one-step synthesis, and the specificity of reaction is good.
Description
Technical field
The present invention relates to a kind of preparation process of pyridine derivate, more particularly to one synthesis 2-（3- alkyl phenoxies）Pyridine
The technique of derivative, belongs to chemical field.
Background technology
2-（3- alkyl phenoxies）Pyridine derivate is a kind of important compound for being largely present in nature.Traditional virtue
The electrophilic alkylated reaction of aroma compounds mainly obtains ortho position and aligns alkylated product, and this alkylated product of meta position closes
At extremely complex, it is difficult to directly be synthesized by fragrant electrophilic substitution reaction, it usually needs the introducing of substituent group and remove into
Row assists synthesis.
Invention content
The purpose of the present invention is to solve 2-（3- alkyl phenoxies）Pyridine derivate is difficult to composition problem, provides a kind of synthesis
2-（3- alkyl phenoxies）The technique of pyridine derivate.
To achieve the purpose of the present invention, following technical solutions is used：A kind of 2-（3- alkyl phenoxies）It is pyridine derived
The preparation method of object, the 2-（3- alkyl phenoxies）Pyridine derivate is the structure of formula III, using the 2- benzene oxygen of structure shown in formula I
Pyridine derivative reacts preparation with the brominated methans compound of formula II, and the brominated methans compound is two or three-level bromo
Alkyl compound, reaction equation are as follows：
Wherein： R1For alkyl or hydrogen, R2For hydrogen or methyl or methoxy, R3、R4、R5For hydrogen or alkyl or ester group or ether,
Reaction process is：By 2- phenoxypyridine derivatives, two or three-level brominated methans compound, catalyst, additive, alkali and molten
Agent is directly added into reaction unit, and the catalyst is bis- (the 4- isopropyl methyls phenyl) rutheniums of dichloro；Alkali is potassium carbonate or carbon
Sour lithium, the additive are 1- adamantane acids or naphthenic acid；The solvent is benzene or DMF or glycol dimethyl ether, stirring
Heating temperature is reacted 12-48 hours, separation product obtains 2- to 80 DEG C -140 DEG C（3- alkyl phenoxies）Pyridine derivate, into
One step, the mole dosage of brominated methans compound is 1-6 times of phenoxypyridines molal quantity, further, described two or
Three-level brominated methans compound is 2 bromo pentane or 3- bromo pentane silanes or tert-bromo butane or 4- bromines oxinane or 2 bromopropionic acid first
Ester.
The positive advantageous effects of the present invention are：This reaction can be with one-step synthesis, and the specificity of reaction is good, changes
2-（3- alkyl phenoxies）Pyridine derivate is difficult to the present situation synthesized, cost-efficiently can obtain 2-（3- alkyl phenoxies）
Pyridine derivate.
Specific implementation mode
In order to more fully explain the implementation of the present invention, the embodiment of the present invention is provided, these embodiments are only
Elaboration to the present invention, does not limit the scope of the invention.
Embodiment 1：
34mg (0.2mmol) 2- phenoxypyridines, 90mg are added in 20mL pressure resistance reaction tubes（0.6 mmol）3- bromines
Pentane, bis- (the 4- isopropyl methyls phenyl) rutheniums of 6mg (0.01mmol) dichloro, 55mg（0.4mmol）Potassium carbonate, 11mg
（0.06mmol）1- adamantane acids, 1.5mL benzene seal under condition of nitrogen gas, are heated to 120 DEG C of reactions, stir 24 hours, reaction
Afterwards, pillar layer separation obtains target product 2-（3-（3- amyls）Phenoxy group）35mg, yield 73%.
Embodiment 2：
40mg (0.2mmol) 2- is added in 20mL pressure resistance reaction tubes（4- methoxyphenoxies）Pyridine, 90mg（0.6
mmol）3- bromo pentane silanes, bis- (the 4- isopropyl methyls phenyl) rutheniums of 6mg (0.01mmol) dichloro, 55mg（0.4mmol）Potassium carbonate,
11mg（0.06mmol）1- adamantane acids, 1.5mL benzene seal under condition of nitrogen gas, are heated to 120 DEG C of reactions, stir 24 hours,
After reaction, pillar layer separation obtains target product 2-（3- amyl -4- methoxyphenoxies）Pyridine 44mg, yield 81%.
Embodiment 3：
34mg (0.2mmol) phenoxypyridines, 82mg are added in 20mL pressure resistance reaction tubes（0.6 mmol）Bromo uncle
Butane, bis- (the 4- isopropyl methyls phenyl) rutheniums of 6mg (0.01mmol) dichloro, 55mg（0.4mmol）Potassium carbonate, 11mg
（0.06mmol）1- adamantane acids, 1.5mL benzene seal under condition of nitrogen gas, are heated to 120 DEG C of reactions, stir 24 hours, reaction
Afterwards, pillar layer separation obtains target product 2-（3- tert-butyl benzene oxygroups）Pyridine 25mg, yield 56%.
Embodiment 4：
40mg (0.2mmol) 2- is added in 20mL pressure resistance reaction tubes（4- methoxyphenoxies）Pyridine, 99mg（0.6
mmol）4- bromine oxinanes, bis- (the 4- isopropyl methyls phenyl) rutheniums of 6mg (0.01mmol) dichloro, 55mg（0.4mmol）Carbonic acid
Potassium, 11mg（0.06mmol）1- adamantane acids, 1.5mL benzene seal under condition of nitrogen gas, are heated to 120 DEG C of reactions, and stirring 24 is small
When, after reaction, pillar layer separation obtains target product 2-（4- oxinane phenoxyls）Pyridine 33mg, yield 58%.
Embodiment 5：
37mg (0.2mmol) 5- methyl -2- phenoxypyridines, 98mg are added in 20mL pressure resistance reaction tubes（0.6 mmol）
2 bromo pentane, 55mg（0.4mmol）Potassium carbonate, 11mg（0.06mmol）1- adamantane acids, 1.5mL benzene are close under condition of nitrogen gas
Envelope is heated to 120 DEG C of reactions, stirs 24 hours, after reaction, pillar layer separation obtains target product 5- methyl -2-（2- amylbenzenes
Oxygroup）Pyridine 24mg, yield 46%.
Embodiment 6：
37mg (0.2mmol) 2- is added in 20mL pressure resistance reaction tubes（4- methylphenoxies）Pyridine, 100mg（0.6
mmol）2 bromopropionic acid methyl esters, 55mg（0.4mmol）Potassium carbonate, 11mg（0.06mmol）1- adamantane acids, 1.5mL benzene, nitrogen
Under the conditions of seal, be heated to 120 DEG C reaction, stir 24 hours, after reaction, pillar layer separation obtains target product 2-（2- methyl-
5-（2- pyridine oxygroups）Phenylpropionic acid methyl ester 18mg, yield 34%.
Embodiment 7：
49mg (0.2mmol) 2- is added in 20mL pressure resistance reaction tubes（4- phenyl phenoxyls）Pyridine, 100mg（0.6
mmol）2 bromopropionic acid methyl esters, 55mg（0.4mmol）Potassium carbonate, 11mg（0.06mmol）1- adamantane acids, 1.5mL benzene, nitrogen
Under the conditions of seal, be heated to 120 DEG C reaction, stir 24 hours, after reaction, pillar layer separation obtains target product 2-（2- just oneself
Base -4- methoxyphenoxies）Pyridine 22mg, yield 33%.
Embodiment 8：
34mg (0.2mmol) 2- phenoxypyridines, 150mg are added in 20mL pressure resistance reaction tubes（1 mmol）2- bromines penta
Alkane, 55mg（0.4mmol）Lithium carbonate, 8mg（0.06mmol）Naphthenic acid, 1.5mL glycol dimethyl ethers, under condition of nitrogen gas
Sealing is heated to 110 DEG C of reactions, stirs 48 hours, after reaction, pillar layer separation obtains target product 2-（3- amyl phenoxy groups）
Pyridine 13mg, yield 28%.
Table one：
Why reaction in the application can be realized more single-minded by 2, its mechanism is still unknown in R groups whole
Really, in order to verify whether the reaction is suitable for other pyridines, following comparative example has also been carried out：
Comparative example 1：2- thiophenyl pyridines substitute 2- phenoxypyridines
37mg (0.2mmol) 2- thiophenyl pyridines, 90mg are added in 20mL pressure resistance reaction tubes（0.6 mmol）3- bromines penta
Alkane, 55mg（0.4mmol）Potassium carbonate, 11mg（0.06mmol）1- adamantane acids, 1.5mL benzene seal under condition of nitrogen gas, heat
It is reacted to 120 DEG C, stirs 24 hours, after reaction, through Mass Spectrometer Method, do not find the substance with molecular weight with target product..
Comparative example 2：2- benzyl pyridines substitute 2- phenoxypyridines
34mg (0.2mmol) 2- benzyl pyridines, 90mg are added in 20mL pressure resistance reaction tubes（0.6 mmol）3- bromines penta
Alkane, 55mg（0.4mmol）Potassium carbonate, 11mg（0.06mmol）1- adamantane acids, 1.5mL benzene seal under condition of nitrogen gas, heat
It is reacted to 120 DEG C, stirs 24 hours, after reaction, through Mass Spectrometer Method, do not find the substance with molecular weight with target product.
Comparative example 3：2- aniline yl pyridines substitute 2- phenoxypyridines
34mg (0.2mmol) 2- aniline yl pyridines, 90mg are added in 20mL pressure resistance reaction tubes（0.6 mmol）3- bromines penta
Alkane, 55mg（0.4mmol）Potassium carbonate, 11mg（0.06mmol）1- adamantane acids, 1.5mL benzene seal under condition of nitrogen gas, heat
It is reacted to 120 DEG C, stirs 24 hours, after reaction, through Mass Spectrometer Method, do not find the substance with molecular weight with target product.
It is same that with dichloro bis- (4- isopropyl methyls phenyl), ruthenium makees catalyst, toluene or acetonitrile or dioxane makees solvent
Under the conditions of, 2- thiophenyls pyridine, 2- benzyl pyridines etc. and the meta position alkylated reaction of two level brominated methans compound cannot be sent out
It is raw, after this explanation substitutes the O for connecting phenyl ring and pyridine in the application using C or S or N, it is anti-ortho-alkylating can not to occur
It answers, illustrate this reaction has the particularity of its own, and mechanism is not clear, can not be pushed away from using conventional similar reaction
Go out, can not also be extrapolated to other reactions.
After the embodiment that the present invention will be described in detail, one of ordinary skilled in the art is clearly understood that, is not taking off
It is lower from above-mentioned claim and spirit to carry out various change and modification, it is all according to the technical essence of the invention to it is above in fact
Any simple modification, equivalent change and modification made by example are applied, belong to the range of technical solution of the present invention, and the present invention is also not
It is limited to the embodiment of example in specification.
Claims (2)
1. a kind of 2-（3- alkyl phenoxies）The preparation method of pyridine derivate, the 2-（3- alkyl phenoxies）It is pyridine derived
Object is the structure of formula III, reacts preparation, institute with II brominated methans compound of formula using the 2- phenoxypyridine derivatives of structure shown in formula I
The brominated methans compound stated is that two or three-level brominated methans compound, reaction equation are as follows：
Wherein： R1For alkyl or hydrogen, R2For hydrogen or methyl or methoxy, R3、R4、R5For hydrogen or alkyl or ester group or ether, reaction
Process is：2- phenoxypyridine derivatives, two or three-level brominated methans compound, catalyst, additive, alkali and solvent is straight
It connects and is added in reaction unit, the catalyst is bis- (the 4- isopropyl methyls phenyl) rutheniums of dichloro；Alkali be potassium carbonate or lithium carbonate,
The additive is 1- adamantane acids or naphthenic acid；The solvent is benzene or DMF or glycol dimethyl ether, described two or
Three-level brominated methans compound is 2 bromo pentane or 3- bromo pentane silanes or tert-bromo butane or 4- bromines oxinane or 2 bromopropionic acid first
Ester, agitating and heating temperature are reacted 12-48 hours, separation product obtains 2- to 80 DEG C -140 DEG C（3- alkyl phenoxies）Pyridine spreads out
Biology.
2. a kind of 2- according to claim 1（3- alkyl phenoxies）The preparation method of pyridine derivate, it is characterised in that：
The mole dosage of brominated methans compound is 1-6 times of phenoxypyridines molal quantity.
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| CN104844399A (en) * | 2015-03-19 | 2015-08-19 | 浙江工业大学 | Method for synthetizing 2-fluoro phenol compound |
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Non-Patent Citations (3)
| Title |
|---|
| Chun Zhang,et al..Palladium-Catalyzed Direct C(sp2)−H Alkoxylation of 2‑Aryloxypyridines Using 2‑Pyridyloxyl as the Directing Group.《The Journal of Organic Chemistry》.2014,第79卷8457−8461. * |
| Gang Li,et al..Synthesis of m‑Alkylphenols via a Ruthenium-Catalyzed C−H Bond Functionalization of Phenol Derivatives.《Organic Letters》.2017,第19卷(第10期),2682−2685. * |
| Yinfeng Xu,et al..Palladium-Catalyzed ortho-Sulfonylation of 2‑Aryloxypyridines and Subsequent Formation of ortho-Sulfonylated Phenols.《The Journal of Organic Chemisty》.2015,第80卷1269−1274. * |
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