CN105439937A - Method for synthesizing 3-halogenoindoles-2-one compound - Google Patents
Method for synthesizing 3-halogenoindoles-2-one compound Download PDFInfo
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- CN105439937A CN105439937A CN201510868724.2A CN201510868724A CN105439937A CN 105439937 A CN105439937 A CN 105439937A CN 201510868724 A CN201510868724 A CN 201510868724A CN 105439937 A CN105439937 A CN 105439937A
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- 0 *N(C(C=N)=O)c1ccccc1 Chemical compound *N(C(C=N)=O)c1ccccc1 0.000 description 2
- LJERJFWMOQMDFP-UHFFFAOYSA-N CN(C(C(c1c2)Br)=O)c1ccc2Br Chemical compound CN(C(C(c1c2)Br)=O)c1ccc2Br LJERJFWMOQMDFP-UHFFFAOYSA-N 0.000 description 1
- JUZJMHVBHXWYRB-UHFFFAOYSA-N CN(C1=O)c2ccccc2C1F Chemical compound CN(C1=O)c2ccccc2C1F JUZJMHVBHXWYRB-UHFFFAOYSA-N 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
- C07D209/32—Oxygen atoms
- C07D209/34—Oxygen atoms in position 2
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Abstract
The invention belongs to the technical field of synthesis of chemical intermediates and particularly relates to a method for synthesizing a 3-halogenoindoles-2-one compound. According to the method, a diazo compound and a halogenating reagent are taken as raw materials, a crude product of the 3-halogenoindoles-2-one compound is obtained through one-step reaction in different organic solvents and at different temperatures under the condition that no catalyst is added, the crude product is subjected to column chromatography by the aid of a mixed solution of ethyl acetate and petroleum ether, and a pure product of the 3-halogenoindoles-2-one compound is obtained. The method has the advantages that no catalyst is used, the raw materials are cheap and easy to obtain, the yield is high, the reaction time is short and operation is simple and safe, and the 3-halogenoindoles-2-one compound obtained with the method is an important chemical and medical intermediate and is widely applied to the field of the medical and chemical industry.
Description
Technical field
The invention belongs to chemical intermediate synthesis technical field, particularly relate to a kind of method of synthesizing 3-halogeno indole-2-ketone compounds.
Background technology
3,3-disubstituted indole compounds is that a class builds the basic framework with bioactive compounds, and occurring in nature exists many materials containing this type of structural unit.In the past few years, effectively the method for synthesis 3 functionalization Benzazole compounds mainly contains oxindolylideneacetate cycloaddition, the nucleophilic addition(Adn) of oxyindole compounds, the electrophilic addition of 3-halogeno indole compounds.These report in, by 3-halogeno indole compounds as electrophilic reagent synthesize 3-replace or the dibasic compound of 3,3-have certain limitation, major cause is difficult to obtain functional group's diversified 3-halogeno indole compounds.Therefore, the method finding efficient synthesis functional group diversified 3-halogeno indole compounds becomes the vital task of researcher.
Because above-mentioned defect, the design people, actively in addition research and innovation, to founding a kind of method of synthesizing 3-halogeno indole-2-ketone compounds, make it have more utility value in industry.
Summary of the invention
For solving the problems of the technologies described above, the object of this invention is to provide a kind of method of synthesizing 3-halogeno indole-2-ketone compounds, the method cost is low, productive rate is high, substrate applicability is wide, simple to operate.
A kind of method of synthesizing 3-halogeno indole-2-ketone compounds that the present invention proposes, comprises the following steps:
(1) getting halogenating agent adds in reaction flask, adds organic solvent dissolution, then, joins in reaction system by the diazonium compound dissolved in organic solvent, stirs, except desolventizing after reaction terminates, obtain crude product;
(2) mixing solutions of crude product ethyl acetate and sherwood oil is carried out column chromatography, obtain straight product;
Described diazonium compound has following general structure, wherein, and R
1any one in alkyl, thiazolinyl, alkynyl, ester group, aromatic group, heterocyclic group; R
2any one in hydrogen, halogen, alkyl, hydroxyl, methoxyl group, trifluoromethyl, aromatic group, heterocyclic group.
Further, the mol ratio of described diazonium compound and halogenating agent is 1:0.8 ~ 1:1.2.
Further, in described step (1), the temperature of reaction is-40 ~ 100 DEG C.
Further, in described step (1), the time of stirring is 0.5 ~ 5h.
Further, the volume ratio of ethyl acetate and sherwood oil is 1:10 ~ 1:2.
Further, the consumption of organic solvent of dissolving halogenating agent is 5 ~ 20mL/mmol halogenating agent, is 5 ~ 20mL/mmol diazonium compound for dissolving the consumption of organic solvent of diazonium compound.
Further, described organic solvent is acetonitrile, methylene dichloride, 1,2-ethylene dichloride, trichloromethane, ether, methyl alcohol, ethanol, tetrahydrofuran (THF), toluene, halogeno-benzene, any one in methyl tertiary butyl ether, 2,2-dimethylbutanes.
Further, described halogenating agent is any one in N-bromosuccinimide, N-chlorosuccinimide, the two benzsulfamide of N-fluoro.
The reaction equation of the 3-halogeno indole-2-ketone compounds of the present invention's synthesis is as follows:
R wherein
1, R
2with the R in said structure general formula
1, R
2identical, NXS:N-halosuccinimides (X=Br, Cl), the two benzsulfamide of NFSI:N-fluoro.
Chemical reaction mechanism involved in the present invention is shown below:
Halogenating agent in-situ preparation halogen positive ion, the carbon of nucleophilicity that what attack was connected with diazonium have forms intermediate 2, and intermediate 2 intramolecular F-C addition reaction occurs and obtains 3-halogeno indole-2-ketone compounds.
By such scheme, the present invention at least has the following advantages: the present invention adopts the diazonium compound of different substituents and halogenating agent directly to react when catalyst-free participates in, have cheaper starting materials be easy to get, simple to operate safe, without the need to catalyzer, the advantages such as functional group's diversified 3-halogeno indole compounds can be obtained by the mode of environmental protection.
Above-mentioned explanation is only the general introduction of technical solution of the present invention, in order to better understand technique means of the present invention, and can be implemented according to the content of specification sheets, be described in detail as follows below with preferred embodiment of the present invention.
Embodiment
Below in conjunction with embodiment, the specific embodiment of the present invention is described in further detail.Following examples for illustration of the present invention, but are not used for limiting the scope of the invention.
Embodiment 1
N-bromosuccinimide (0.2mmol) is added in reaction flask, add 10mL acetonitrile under room temperature condition and dissolve N-bromosuccinimide, under agitation condition, 2-diazo-N-methyl-N-phenylacetamide (0.2mmol) be dissolved in 10mL acetonitrile is added in reaction system.Stirring at room temperature 1 hour, removal of solvent under reduced pressure, obtains crude product.Crude product is carried out column chromatography purification (ethyl acetate: sherwood oil=1:10) and obtain the bromo-1-skatole of 3--2-ketone compound, white solid, productive rate is 97%.Product chemistry structural formula is as follows:
Embodiment 2
N-bromosuccinimide (0.2mmol) is added in reaction flask, add 10mL acetonitrile under room temperature condition and dissolve N-bromosuccinimide, under agitation condition, N-4-bromophenyl-2-diazo-N-methylacetamide (0.18mmol) be dissolved in 10mL acetonitrile is added in reaction system.Stirring at room temperature 1 hour, removal of solvent under reduced pressure, obtains crude product.Crude product is carried out column chromatography purification (ethyl acetate: sherwood oil=1:10) and obtain the bromo-1-skatole of 3,5-bis--2-ketone compound.White solid, productive rate is 85%.Product chemistry structural formula is as follows:
Embodiment 3
N-bromosuccinimide (0.2mmol) is added in reaction flask, add 10mL methylene dichloride under room temperature condition and dissolve N-bromosuccinimide, under agitation condition, 2-diazo-N-4-p-methoxy-phenyl-N-methylacetamide (0.2mmol) be dissolved in 10mL methylene dichloride is added in reaction system.Stirring at room temperature 1.5 hours, removal of solvent under reduced pressure, obtains crude product.Crude product is carried out column chromatography purification (ethyl acetate: sherwood oil=1:5) and obtain the bromo-5-methoxyl group of 3--1-skatole-2-ketone compound.White solid, productive rate is 97%.Product chemistry mechanism is as follows:
Embodiment 4
N-bromosuccinimide (0.2mmol) is added in reaction flask, add 5mL acetonitrile under room temperature condition and dissolve N-bromosuccinimide, under agitation condition, 2-diazo-N-methyl-N-4-trifluoromethylbenzene yl acetamide (0.2mmol) be dissolved in 15mL acetonitrile is added in reaction system.Stirring at room temperature 2.5 hours, removal of solvent under reduced pressure, obtains crude product.Crude product is carried out column chromatography purification (ethyl acetate: sherwood oil=1:10) and obtain the bromo-1-methyl of 3--5-trifluoro methyl indole-2-ketone compound.White solid, productive rate is 65%.Product chemistry structural formula is as follows:
Embodiment 5
N-bromosuccinimide (0.2mmol) is added in reaction flask, 10mL1 is added under-40 DEG C of conditions, 2-methylene dichloride dissolves N-bromosuccinimide, to be dissolved in 10mL1 under agitation condition, 2-diazo-N-4-p-methoxy-phenyl-N-methylacetamide (0.2mmol) in 2-methylene dichloride is added in reaction system.-40 DEG C are stirred 5 hours, and removal of solvent under reduced pressure, obtains crude product.Crude product is carried out column chromatography purification (ethyl acetate: sherwood oil=1:2) and obtain the bromo-5-methoxyl group of 3--1-skatole-2-ketone compound.White solid, productive rate is 88%.Product chemistry structural formula is as follows:
Embodiment 6
N-bromosuccinimide (0.2mmol) is added in reaction flask, add 10mL toluene under 0 DEG C of condition and dissolve N-bromosuccinimide, to be dissolved in the 2-diazo-N in 10mL toluene under agitation condition, N diphenylacetamide (0.2mmol) is added in reaction system.0 DEG C is stirred 2 hours, and removal of solvent under reduced pressure, obtains crude product.Crude product is carried out column chromatography purification (ethyl acetate: sherwood oil=1:8) and obtain the bromo-1-Phenylindole of 3--2-ketone compound.White solid, productive rate is 87%.Product chemistry structural formula is as follows:
Embodiment 7
N-bromosuccinimide (0.2mmol) is added in reaction flask, add 5mL acetonitrile under room temperature condition and dissolve N-bromosuccinimide, being added in reaction system by N-benzyl 2-diazo-phenyl acetanilide,Phenacetylaniline (0.25mmol) that be dissolved in 20mL acetonitrile under agitation condition.Stirring at room temperature 2 hours, removal of solvent under reduced pressure, obtains crude product.Crude product is carried out column chromatography purification (ethyl acetate: sherwood oil=1:10) and obtain 1-benzyl-3-bromo indole-2-ketone compound.White solid, productive rate is 90%.Product chemistry structural formula is as follows:
Embodiment 8
N-bromosuccinimide (0.2mmol) is added in reaction flask, add 15mL acetonitrile under room temperature condition and dissolve N-bromosuccinimide, under agitation condition, 2-diazo-N-phenyl-N-propargyl ethanamide (0.22mmol) be dissolved in 15mL acetonitrile is added in reaction system.Stirring at room temperature 2 hours, removal of solvent under reduced pressure, obtains crude product.Crude product is carried out column chromatography purification (ethyl acetate: sherwood oil=1:10) and obtain 1-alkynes third-3-bromo indole-2-ketone compound.White solid, productive rate is 90%.Product chemistry structural formula is as follows:
Embodiment 9
N-bromosuccinimide (0.2mmol) is added in reaction flask, add 10mL acetonitrile under room temperature condition and dissolve N-bromosuccinimide, under agitation condition, the 2-diazo-N-(2-methoxy ethyl)-phenyl acetanilide,Phenacetylaniline (0.2mmol) be dissolved in 10mL acetonitrile is added in reaction system.Stirring at room temperature 2 hours, removal of solvent under reduced pressure, obtains crude product.Crude product is carried out column chromatography purification (ethyl acetate: sherwood oil=1:7) and obtain the bromo-1-of 3-(2-methoxy ethyl) indol-2-one compound.White solid, productive rate is 87%.Product chemistry structural formula is as follows:
Embodiment 10
N-bromosuccinimide (0.2mmol) is added in reaction flask, add 10mL acetonitrile under 30 DEG C of conditions and can dissolve N-bromosuccinimide, under agitation condition, N-cinnamyl-2-diazo-phenyl acetanilide,Phenacetylaniline (0.2mmol) be dissolved in 10mL acetonitrile is added in reaction system.30 DEG C are stirred 2 hours, and removal of solvent under reduced pressure, obtains crude product.Crude product is carried out column chromatography purification (ethyl acetate: sherwood oil=1:10 ~ 1:2) and obtain 3-bromo-1-cinnamyl indol-2-one compound.White solid, productive rate is 80%.Product chemistry structural formula is as follows:
Embodiment 11
N-chlorosuccinimide (0.2mmol) is added in reaction flask, add 10mL acetonitrile under room temperature condition and dissolve N-chlorosuccinimide, under agitation condition, 2-diazo-N-methyl-N-phenylacetamide (0.2mmol) be dissolved in 10mL acetonitrile is added in reaction system.Stirring at room temperature 1 hour, removal of solvent under reduced pressure, obtains crude product.Crude product is carried out column chromatography purification (ethyl acetate: sherwood oil=1:10) and obtain the chloro-1-skatole of 3--2-ketone compound.White solid, productive rate is 77%.Product chemistry structural formula is as follows:
Embodiment 12
Two for N-fluoro benzsulfamide (0.24mmol) is added in reaction flask, add 20mL acetonitrile under 100 DEG C of conditions and dissolve the two benzsulfamide of N-fluoro, under agitation condition, 2-diazo-N-methyl-N-phenylacetamide (0.2mmol) be dissolved in 5mL acetonitrile is added in reaction system.100 DEG C are stirred 0.5 hour, and removal of solvent under reduced pressure, obtains crude product.Crude product is carried out column chromatography purification (ethyl acetate: sherwood oil=1:10) and obtain the fluoro-1-skatole of 3--2-ketone compound.White solid, productive rate is 65%.Product chemistry structural formula is as follows:
In sum, the present invention is under the condition of catalyst-free, by the diazonium compound of different substituents and the direct reaction of halogenating agent, obtain functional group's multifarious 3-halogeno indole compounds, be 3, the synthesis of 3-disubstituted indole compounds is supplied raw materials, and has widened the application of this type of skeletonisation compound, has the advantages such as cheaper starting materials is easy to get, safety simple to operate, high yield simultaneously.
The above is only the preferred embodiment of the present invention; be not limited to the present invention; should be understood that; for those skilled in the art; under the prerequisite not departing from the technology of the present invention principle; can also make some improvement and modification, these improve and modification also should be considered as protection scope of the present invention.
Claims (8)
1. synthesize a method for 3-halogeno indole-2-ketone compounds, it is characterized in that: comprise the following steps:
(1) getting halogenating agent adds in reaction flask, adds organic solvent dissolution, then, joins in reaction system by the diazonium compound dissolved in organic solvent, stirs, except desolventizing after reaction terminates, obtain crude product;
(2) mixing solutions of crude product ethyl acetate and sherwood oil is carried out column chromatography, obtain straight product;
Described diazonium compound has following general structure, wherein, and R
1any one in alkyl, thiazolinyl, alkynyl, ester group, aromatic group, heterocyclic group; R
2any one in hydrogen, halogen, alkyl, hydroxyl, methoxyl group, trifluoromethyl, aromatic group, heterocyclic group.
2. a kind of method of synthesizing 3-halogeno indole-2-ketone compounds according to claim 1, is characterized in that: the mol ratio of described diazonium compound and halogenating agent is 1:0.8 ~ 1:1.2.
3. a kind of method of synthesizing 3-halogeno indole-2-ketone compounds according to claim 2, is characterized in that: in described step (1), and the temperature of reaction is-40 ~ 100 DEG C.
4. a kind of method of synthesizing 3-halogeno indole-2-ketone compounds according to claim 3, is characterized in that: in described step (1), and the time of stirring is 0.5 ~ 5h.
5. a kind of method of synthesizing 3-halogeno indole-2-ketone compounds according to claim 1, is characterized in that: the volume ratio of ethyl acetate and sherwood oil is 1:10 ~ 1:2.
6. a kind of method of synthesizing 3-halogeno indole-2-ketone compounds according to claim 1, it is characterized in that: the consumption of organic solvent of dissolving halogenating agent is 5 ~ 20mL/mmol halogenating agent, is 5 ~ 20mL/mmol diazonium compound for dissolving the consumption of organic solvent of diazonium compound.
7. a kind of method of synthesizing 3-halogeno indole-2-ketone compounds according to claim 1, it is characterized in that: described organic solvent is acetonitrile, methylene dichloride, 1,2-ethylene dichloride, trichloromethane, ether, methyl alcohol, ethanol, tetrahydrofuran (THF), toluene, halogeno-benzene, any one in methyl tertiary butyl ether, 2,2-dimethylbutanes.
8. a kind of method of synthesizing 3-halogeno indole-2-ketone compounds according to claim 1, is characterized in that: described halogenating agent is any one in N-bromosuccinimide, N-chlorosuccinimide, the two benzsulfamide of N-fluoro.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108047120A (en) * | 2018-01-22 | 2018-05-18 | 浙江工业大学 | A kind of method that substituted indole directly synthesizes 3- chlorine producing oxindoles compounds |
| CN108129377A (en) * | 2017-11-21 | 2018-06-08 | 浙江工业大学 | A kind of method that substituted indole directly synthesizes substitution 2- indolones in neutral conditions |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104370797A (en) * | 2014-10-30 | 2015-02-25 | 华东师范大学 | Synthesis method of 3-halooxindole derivatives |
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- 2015-12-02 CN CN201510868724.2A patent/CN105439937A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104370797A (en) * | 2014-10-30 | 2015-02-25 | 华东师范大学 | Synthesis method of 3-halooxindole derivatives |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108129377A (en) * | 2017-11-21 | 2018-06-08 | 浙江工业大学 | A kind of method that substituted indole directly synthesizes substitution 2- indolones in neutral conditions |
| CN108047120A (en) * | 2018-01-22 | 2018-05-18 | 浙江工业大学 | A kind of method that substituted indole directly synthesizes 3- chlorine producing oxindoles compounds |
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Application publication date: 20160330 |