CN106748802B - A method of preparing fluorine-containing secondary amine - Google Patents
A method of preparing fluorine-containing secondary amine Download PDFInfo
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- CN106748802B CN106748802B CN201611220037.0A CN201611220037A CN106748802B CN 106748802 B CN106748802 B CN 106748802B CN 201611220037 A CN201611220037 A CN 201611220037A CN 106748802 B CN106748802 B CN 106748802B
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- fluorine
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- fluorinated alohol
- secondary amine
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
- C07C209/04—Preparation of compounds containing amino groups bound to a carbon skeleton by substitution of functional groups by amino groups
- C07C209/14—Preparation of compounds containing amino groups bound to a carbon skeleton by substitution of functional groups by amino groups by substitution of hydroxy groups or of etherified or esterified hydroxy groups
- C07C209/18—Preparation of compounds containing amino groups bound to a carbon skeleton by substitution of functional groups by amino groups by substitution of hydroxy groups or of etherified or esterified hydroxy groups with formation of amino groups bound to carbon atoms of six-membered aromatic rings or from amines having nitrogen atoms bound to carbon atoms of six-membered aromatic rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
- C07C209/04—Preparation of compounds containing amino groups bound to a carbon skeleton by substitution of functional groups by amino groups
- C07C209/14—Preparation of compounds containing amino groups bound to a carbon skeleton by substitution of functional groups by amino groups by substitution of hydroxy groups or of etherified or esterified hydroxy groups
- C07C209/16—Preparation of compounds containing amino groups bound to a carbon skeleton by substitution of functional groups by amino groups by substitution of hydroxy groups or of etherified or esterified hydroxy groups with formation of amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
- C07C213/02—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton by reactions involving the formation of amino groups from compounds containing hydroxy groups or etherified or esterified hydroxy groups
Abstract
The invention discloses a kind of synthetic methods of fluorine secondary-amine compound.Using pentamethylcyclopentadiene iridium chloride dimer as metallic catalyst, fluorinated alohol is fluoroalkyl source, and alkali prepares fluorine secondary amine through the following steps as co-catalyst：In organic solvent, under the action of transition metal iridium catalyst and alkali, primary amine is reacted with fluorinated alohol, and fluorine-containing secondary-amine compound is made.Method provided by the invention overcomes in the prior art, fluorine-containing alkylating reagent toxicity is big, it is unstable, need to prepare in advance, the defects of operation is complicated, complex steps, and can get considerable yield.The fluorinated alohol of use is easy to get and chemical property is stable, toxicity is low.This method reaction process is simple, has very high Atom economy and step economy, energy conservation and environmental protection easy to operate.Using [Cp*IrCl2]2As catalyst, ligand need not be added in reaction process, system is easy to implement.
Description
Technical field
The invention belongs to organic synthesis fields, and in particular to a method of preparing fluorine-containing secondary amine.
Background technology
Secondary amine is a kind of very important structural unit, is widely present in medicine, pesticide and natural products molecule.Primary amine
Alkylation be prepare secondary amine it is a kind of basis but important means.Since mid-twentieth century, fluorochemical is each
Importance in a field increasingly highlights, especially in life science.According to statistics, be more than 20% approved
The pesticide of the commercialization of drug and 30-40% is fluorine-containing.It is contemplated that containing fluoroalkyl chain if introduced in primary amine, prepare
Fluorine-containing secondary amine be possible to can have certain special pharmaceutical activity.Therefore the research prepared for fluorine-containing secondary amine not only has reason
It is also of far-reaching significance in practical application by upper meaning.
The preparation method of current fluorine-containing secondary amine is mainly as follows：1) halogenated fluorine-containing alkane or quasi- halogenated fluorine-containing alkane are as alkane
Base reagent：Primary amine fluorine-containing secondary amine corresponding with the reaction generation of fluorine-containing alkylating reagent is (such as formula a).The disadvantages of this method is fluorine-containing
The toxicity of halogenated alkane is higher, and the Atom economy of reaction is also poor, and the stoichiometric alkali of spent acid needs of generation, which is used as, ties up acid
Agent.In addition, many fluorine-containing alkylating reagents are not commercially available, need to prepare in advance.2) fluorine-containing fatty aldehyde is as alkylation
Reagent：First with primary amine condensation reaction occurs for fluorine-containing fatty aldehyde, obtains fluorine-containing imine product, then obtain fluorine-containing secondary amine (such as through reduction
Formula b).The defect of the reaction is that reaction needs two steps, and step economy is poor, and fluorine-containing fatty aldehyde is mostly unstable, has and waves
Hair property, and be not mostly commercially available.3) halogen exchange prepares fluorine-containing secondary amine：Primary amine prepares halogenated acyl with halogenated anhydride reaction
Fluoro amide is made through halogen exchange in amine, and fluorine-containing secondary amine most is made (such as formula c) through restoring afterwards.Such reaction disadvantage mainly walks
Rapid cumbersome, efficiency is relatively low.
Transfer hydrogenation amino-alkylation is a kind of relatively new reaction type, and specific reaction mechanism is：In transition gold
Under the action of category, alcohol occurs dehydrogenation and generates aldehyde while generating reducing metal hydride, then in generated in-situ aldehyde and system
Primary amine occur condensation reaction, formed imine intermediate, the metal hydride reduction that last imine intermediate is formed by the first step,
Obtain final alkylate.
Alcohol there is abundance, property to stablize, good economy performance etc. as alkylating reagent compared to aldehyde or halides
Advantage.Using alcohol as alkylating reagent, the alkylated research of primary amine is also become in recent years in transition metal-catalyzed lower realization
The research hotspot come.However, current research is mostly focused on alkylol, aryl alcohol, the substrates such as amino alcohol, for grinding for fluorine alcohol
Study carefully then much less.
Invention content
The object of the present invention is to provide it is a kind of it is transition metal-catalyzed under, fluorinated alohol is fluorine-containing secondary as the synthesis of fluoroalkyl source
The method of aminated compounds.
In order to solve the above-mentioned technical problem it is as follows to provide technical solution：
A method of fluorine-containing secondary amine is prepared, is included the following steps：
The transition metal iridium catalyst of catalytic amount, alkali are mixed and are added in organic solution, under nitrogen protection, is sequentially added
Formulas I primary amine compound, Formula II are fluorinated alcohol compound, and 90-100 DEG C of heating is stirred to react for 24 hours, after reaction, revolving is removed
Solvent, column chromatography is gone to obtain fluorine-containing secondary-amine compound formula III after purification.
Specific reaction equation is as follows：
Substituent R in Formulas I, Formula II, Rf is respectively independent, and R is selected from aryl, C3~C10Alkyl, C3~C10Alkoxy,
It is CH that Rf, which is selected from end,2F、CHF2Or CF3Contain fluoroalkyl chain.
The present invention compares compared with the existing technology, has remarkable advantage：
(1) the present invention overcomes in the prior art, fluorine-containing alkylating reagent toxicity is big, it is unstable, need to prepare in advance, instead
It answers complicated for operation, the defects of complex steps, and can get considerable yield.
(2) fluoroalkylation reagent is fluorinated alohol in method provided by the invention, such reagent has realized commercialization, has been easy to obtain
And chemical property is stable, toxicity is low.Meanwhile one step of this method can be completed to react, have very high Atom economy and
Step economy, energy conservation and environmental protection are easy to operate.It realizes the direct fluoroalkylation of primary amine compound and prepares fluorine-containing secondary amine class chemical combination
Object.
(3) [the Cp*IrCl of commodity in use2]2As catalyst, ligand need not be added in reaction process, system is held
Easily realize.
Specific implementation mode
It is further illustrated the present invention below by the mode of embodiment, but does not therefore limit the present invention to the reality
It applies among a range.
Embodiment 1
Under nitrogen protection, [Cp*IrCl is sequentially added into pressure pipe2]20.006mmol, aniline 0.3mmol, fluorine second
Alcohol 0.33mmol, sodium bicarbonate 0.006mmol and toluene 0.5mL are heated to 100 DEG C and react for 24 hours.After reaction, it is down to
A small amount of water is added in room temperature, and 15mL ethyl acetate extracts three times, merges organic phase, then saturated common salt water washing, anhydrous slufuric acid
Magnesium is dried, and removes solvent under reduced pressure, it is 76% that column chromatography for separation, which obtains secondary amine yield,
Embodiment 2
Under nitrogen protection, [Cp*IrCl is sequentially added into pressure pipe2]20.006mmol, 0.3 mmol of aniline, fluorine second
Alcohol 0.33mmol, triethylamine 0.03mmol and toluene 0.5mL are heated to 100 DEG C and react for 24 hours.After reaction, it is down to room
A small amount of water is added in temperature, and 15mL ethyl acetate extracts three times, merges organic phase, then saturated common salt water washing, anhydrous magnesium sulfate is dry
It is dry, remove solvent under reduced pressure, it is 75% that column chromatography for separation, which obtains secondary amine yield,.
Embodiment 3
Under nitrogen protection, [Cp*IrCl is sequentially added into pressure pipe2]20.006mmol, 0.3 mmol of aniline, fluorine second
Alcohol 0.33mmol, sodium bicarbonate 0.006mmol and dioxane 0.5mL are heated to 100 DEG C and react for 24 hours.After reaction,
It is down to room temperature, a small amount of water is added, 15mL ethyl acetate extracts three times, merges organic phase, then saturated common salt water washing, anhydrous
Magnesium sulfate is dried, and removes solvent under reduced pressure, it is 75% that column chromatography for separation, which obtains secondary amine yield,.
Embodiment 4
Under nitrogen protection, [Cp*IrCl is sequentially added into pressure pipe2]20.006mmol, 0.3 mmol of aniline, fluorine second
Alcohol 0.33mmol, sodium bicarbonate 0.006mmol and tert-pentyl alcohol 0.5mL are heated to 100 DEG C and react for 24 hours.After reaction, it drops
To room temperature, a small amount of water is added, 15 mL ethyl acetate extract three times, merge organic phase, then saturated common salt water washing, anhydrous sulphur
Sour magnesium drying removes solvent under reduced pressure, and it is 79% that column chromatography for separation, which obtains secondary amine yield,.
Embodiment 5
Under nitrogen protection, [Cp*IrCl is sequentially added into pressure pipe2]20.006mmol, n-amylamine 0.3mmol, fluorine second
Alcohol 0.33mmol, sodium bicarbonate 0.006mmol and tert-pentyl alcohol 0.5mL are heated to 100 DEG C and react for 24 hours.After reaction, it drops
To room temperature, a small amount of water is added, 15mL ethyl acetate extracts three times, merges organic phase, then saturated common salt water washing, anhydrous sulphur
Sour magnesium drying removes solvent under reduced pressure, and it is 70% that column chromatography for separation, which obtains secondary amine yield,.
Embodiment 6
Under nitrogen protection, [Cp*IrCl is sequentially added into pressure pipe2]20.006mmol, 2- phenoxyethylamine
0.3mmol, fluoroethanol 0.33mmol, sodium bicarbonate 0.006mmol and tert-pentyl alcohol 0.5mL are heated to 100 DEG C and react for 24 hours.
After reaction, it is down to room temperature, a small amount of water is added, 15mL ethyl acetate extracts three times, merges organic phase, then saturated salt solution
Washing, anhydrous magnesium sulfate drying remove solvent under reduced pressure, and it is 81% that column chromatography for separation, which obtains secondary amine yield,.
Embodiment 7
Under nitrogen protection, [Cp*IrCl is sequentially added into pressure pipe2]20.006mmol, aniline 0.3 mmol, 3,3,
3- tri- fluoro- 1- propyl alcohol 0.33mmol, sodium bicarbonate 0.006mmol and tert-pentyl alcohol 0.5mL are heated to 100 DEG C and react for 24 hours.Instead
After answering, it is down to room temperature, a small amount of water is added, 15mL ethyl acetate extracts three times, merges organic phase, then saturated common salt is washed
It washs, anhydrous magnesium sulfate drying, removes solvent under reduced pressure, it is 75% that column chromatography for separation, which obtains secondary amine yield,.
Embodiment 8
Under nitrogen protection, [Cp*IrCl is sequentially added into pressure pipe2]20.006mmol, aniline 0.3mmol, 3,3,
3- tri- fluoro- n-butyl alcohol 0.33mmol, sodium bicarbonate 0.006mmol and tert-pentyl alcohol 0.5mL are heated to 100 DEG C and react for 24 hours.Instead
After answering, it is down to room temperature, a small amount of water is added, 15mL ethyl acetate extracts three times, merges organic phase, then saturated common salt is washed
It washs, anhydrous magnesium sulfate drying, removes solvent under reduced pressure, it is 83% that column chromatography for separation, which obtains secondary amine yield,.
Embodiment 9
Under nitrogen protection, [Cp*IrCl is sequentially added into pressure pipe2]20.006mmol, aniline 0.3mmol, 3,3-
Two fluoro- 1- propyl alcohol 0.45mmol, sodium bicarbonate 0.006mmol and tert-pentyl alcohol 0.5mL are heated to 100 DEG C and react for 24 hours.Reaction
After, it is down to room temperature, a small amount of water is added, 15mL ethyl acetate extracts three times, merges organic phase, then saturated common salt is washed
It washs, anhydrous magnesium sulfate drying, removes solvent under reduced pressure, it is 45% that column chromatography for separation, which obtains secondary amine yield,.
Embodiment 10
Under nitrogen protection, [Cp*IrCl is sequentially added into pressure pipe2]20.006mmol, aniline 0.3mmol, 3,3-
Two fluoro- 1- propyl alcohol 0.33mmol, sodium bicarbonate 0.006mmol and tert-pentyl alcohol 0.5mL are heated to 90 DEG C and react for 24 hours.Reaction knot
Shu Hou is down to room temperature, and a small amount of water is added, and 15mL ethyl acetate extracts three times, merges organic phase, then saturated common salt water washing,
Anhydrous magnesium sulfate is dried, and removes solvent under reduced pressure, it is 85% that column chromatography for separation, which obtains secondary amine yield,.
Claims (5)
1. a kind of method preparing fluorine-containing secondary amine, which is characterized in that include the following steps：
The transition metal iridium catalyst of catalytic amount, alkali are mixed into addition organic solvent and sequentially add primary amine I under nitrogen protection,
Fluorinated alohol II is heated to 90-100 DEG C and is stirred to react for 24 hours, and after reaction, revolving removes solvent, and column chromatography is contained after purification
Fluorine secondary-amine compound III；
Specific reaction equation is as follows：
The fluorinated alohol II is fluoroethanol, tri- fluoro- 1- fourths of tri- fluoro- 1- propyl alcohol of 3,3,3-, bis- fluoro- 1- propyl alcohol of 3,3- or 3,3,3-
Alcohol, Formulas I substituent R, R are selected from aryl, C3~C10Alkyl, C3~C10Alkoxy；The transition metal iridium catalyst is
[Cp*IrCl2]2。
2. according to the method described in claim 1, it is characterized in that：The alkali is sodium bicarbonate or triethylamine.
3. according to the method described in claim 1, it is characterized in that：The primary amine is aromatic amine or fatty amine.
4. according to the method described in claim 1, it is characterized in that：The organic solvent be toluene, dioxane or uncle
Amylalcohol.
5. according to the method described in claim 1, it is characterized in that：The molar ratio of the primary amine and fluorinated alohol is 1:1.1 extremely
1:1.5。
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| CN102834379A (en) * | 2010-03-26 | 2012-12-19 | 通用电气健康护理有限公司 | Tricyclic indole derivatives as PBR ligands |
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| CN102321046B (en) * | 2011-07-29 | 2014-03-26 | 南京理工大学 | Method for preparing 2-(N-alkyl)aminothiazole and 2-(N-alkyl) aminooxazole derivative by N-alkylation reaction |
| CN103172523B (en) * | 2011-12-23 | 2015-09-30 | 南京理工大学 | The method of the selective N-primary amine that methylates |
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| CN102834379A (en) * | 2010-03-26 | 2012-12-19 | 通用电气健康护理有限公司 | Tricyclic indole derivatives as PBR ligands |
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| Simple andefficient synthesisof2-[18F]fluoroethyltriflate for highyield 18fluoroethylation;TanjaPeters等;《Applied RadiationandIsotopes》;20140804;第94卷;第142页右栏倒数第1-2段 * |
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