CN104592089A - Catalytic synthesis of 3-amino-alkylindole by using [HMim] BF4 ionic liquid in water - Google Patents

Catalytic synthesis of 3-amino-alkylindole by using [HMim] BF4 ionic liquid in water Download PDF

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Publication number
CN104592089A
CN104592089A CN201510011882.6A CN201510011882A CN104592089A CN 104592089 A CN104592089 A CN 104592089A CN 201510011882 A CN201510011882 A CN 201510011882A CN 104592089 A CN104592089 A CN 104592089A
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hmim
ionic liquid
aromatic aldehyde
indoles
water
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CN201510011882.6A
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CN104592089B (en
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杜玉英
张晶
韩利民
田福利
赵霜
竺宁
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Inner Mongolia University of Technology
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Inner Mongolia University of Technology
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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
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/14—Radicals substituted by nitrogen atoms, not forming part of a nitro radical

Abstract

The invention relates to a method for synthesizing an organic synthetic intermediate 3-amino-alkylindole. The [HMim] BF4 ionic liquid serves as a catalyst, and the 3-amino-alkylindole is synthesized from aromatic aldehyde, indole and secondary amine in water by virtue of a one-pot process. The method disclosed by the invention has the advantages that the catalyst is safe, readily available and environment-friendly and can be recycled, the reaction conditions are mild, the operation is simple and convenient, the yield is high and the like.

Description

[HMim] BF in water 4ionic liquid-catalyzed synthesis 3-amine alkyl-indol
Technical field
The present invention relates to a kind of synthetic method of indole derivatives, particularly relate to one [HMim] BF in water 4ionic liquid-catalyzed method of being synthesized 3-amine alkyl-indol by aromatic aldehyde, indoles and methylphenylamine.
Background technology
Indole structure unit is important pharmaceutical intermediate.The natural indole derivatives of known kind more than 3000 at present, have kind more than 40 to be therapeutic type medicine, wherein 3-substituted indole derivative occupies certain ratio, and such as N-dimethylserotonin has anesthetic action; Psilocybin is that some toadstool causes unreal composition; Tryptophane is necessary amino acid; Brazil's alkali is the phytoalexin of opposing microbial challenge; 5-hydroxyl look ammonia derivative can treat migraine; 3-indolyl acetic acid derivative is used for the treatment of rheumatic arthritis etc.
Along with environmental carrying capacity reaches capacity, green solvent becomes the important development direction of Green Chemistry, and ionic liquid receives much concern as green solvent and medium always.The present invention take ionic liquid as the synthesis that catalyzer completes 3-amine alkyl-indol in water, and mild condition is environmentally friendly.
Summary of the invention
The object of this invention is to provide one [HMim] BF 4ionic liquid is catalyzer, completes in water, and with aromatic aldehyde, indoles and methylphenylamine for raw material, one kettle way gentleness prepares the method for 3-amine alkyl-indol.
Technical solution of the present invention is as follows:
Aromatic aldehyde, indoles and methylphenylamine are directly blended in water by the present invention, with [HMim] BF 4ionic liquid is as catalyzer, and stirring reaction synthesizes 3-amine alkyl-indol.Wherein said indoles is the indoles of various replacement, its R 1for hydrogen, bromine, methoxyl group; Wherein said aromatic aldehyde is the aromatic aldehyde of various replacement, its R 2for hydrogen or monosubstituted, polysubstituted halogen, alkoxyl group, hydroxyl or nitro.Reaction formula of the present invention is as follows:
The present invention synthesizes the method for 3-amine alkyl-indol, and step is as follows:
1) in reaction flask, add aromatic aldehyde, methylphenylamine, indoles, catalyzer [HMim] BF 4ionic liquid and a small amount of water, wherein aromatic aldehyde: methylphenylamine: the mol ratio of indoles is 1: 1.0 ~ 2.0: 1, aromatic aldehyde and [HMim] BF 4stirring reaction 3-12 hour when the mol ratio of ionic liquid is 1: 0.1,60 DEG C, TLC follows the tracks of reaction.
2) reaction adds extraction into ethyl acetate after terminating and uses anhydrous sodium sulfate drying organic phase, steams after desolventizing and obtains crude product.Crude product sherwood oil and ethyl acetate are done after eluent carries out column chromatography for separation and are obtained red brown solid 3-amine alkyl-indol.Aqueous phase after drying, [HMim] BF 4ionic liquid can be recycled at least 4 productive rates without obvious reduction.
Described step 1) preferably aromatic aldehyde, methylphenylamine and indoles mol ratio are 1: 2: 1;
Preferably, described step 1) catalyzer [HMim] BF 4ionic liquid is 10% relative to the molecular fraction of aromatic aldehyde.
Described step 2) [HMim] BF 4ionic liquid can be recycled at least 4 productive rates without obvious reduction.
The present invention has catalyst safety and is easy to get, and can be recycled, environmentally friendly, water as solvent, and reaction conditions is gentle, easy and simple to handle, productive rate advantages of higher.
Embodiment
Below in conjunction with embodiment, the present invention is described further, but be not limited thereto.
The synthesis of embodiment 1, N-(3-indyl-phenyl) methyl-N-methyl aniline, structural formula is:
1.0mmol phenyl aldehyde, 2mmol methylphenylamine, 1.0mmol indoles, 0.1mmol [HMim] BF is added in 25ml round-bottomed flask 4ionic liquid and 0.5ml water, stirring reaction 4 hours when 60 DEG C, the completely rear stopped reaction of TLC detection reaction.After being cooled to room temperature, adding extraction into ethyl acetate and use anhydrous sodium sulfate drying organic phase, adopting Rotary Evaporators removing solvent ethyl acetate to obtain crude product.Crude product ethyl acetate and sherwood oil do eluent (ethyl acetate: sherwood oil=1: 4), adopt gradient elution, after carrying out column chromatography for separation (200-300 order silica gel), obtain red brown solid N-(3-indyl-phenyl) the methyl-N-methyl aniline 287.4mg that purity is 99%, isolated yield is 92.0%, and fusing point is 129-130 DEG C.
Infrared spectrogram IR (KBr) v:736,1455,1507,1610,2925,3041,3361,3405cm -1.
Nuclear magnetic resonance data: 1h NMR (500MHz, CDCl 3): δ 2.78 (s, 3H), 5.56 (s, 1H), 6.53 (d, J=8.0Hz, 3H), 6.68-6.81 (m, 3H), 7.05 (d, J=10.0Hz, 2H), 7.16-7.39 (m, 6H), 7.56 (s, 1H), 7.85 (s, 1H); 13c NMR (125MHz, CDCl 3): δ 30.5,47.9,111.1,112.3,119.1,119.9,122.0,123.9,126.9,128.0,128.8,129.6,130.2,133.0,136.5,144.8,147.6.
Product is consistent with bibliographical information through qualification.
The synthesis of embodiment 2, N-(3-indyl-(4-nitrophenyl)) methyl-N-methyl aniline, structural formula is:
1.0mmol paranitrobenzaldehyde, 2mmol methylphenylamine, 1.0mmol indoles, 0.1mmol [HMim] BF is added in 25ml round-bottomed flask 4ionic liquid and 0.5ml water, stirring reaction 3 hours when 60 DEG C.All the other steps are with embodiment 1, and obtain red brown solid N-(3-indyl-(4-nitrophenyl)) the methyl-N-methyl aniline 321.7mg that purity is 99%, isolated yield is 90.0%, and fusing point is 60-62 DEG C.
Infrared spectrogram IR (KBr) v:741,1345,1459,1520,1609,2929,3408cm -1.
Nuclear magnetic resonance data: 1h NMR (500MHz, CDCl 3): δ 2.83 (s, 3H), 5.58 (s, 1H), 6.51-6.55 (m, 3H), 6.90-6.99 (m, 3H), 7.10-7.18 (m, 2H), 7.27-7.51 (m, 4H), 8.01 (s, 1H), 8.15 (d, J=10.0Hz, 2H); 13c NMR (125MHz, CDCl 3): δ 31.0,47.8,111.0,112.4,119.5,120.1,122.2,123.6,124.0,126.8,129.3,130.9,136.6,146.3,147.8,152.3.
Product is consistent with bibliographical information through qualification.
The synthesis of embodiment 3, N-((5-bromo-3-indyl)-phenyl) methyl-N-methyl aniline, structural formula is:
1.0mmol phenyl aldehyde, 2mmol methylphenylamine, 1.0mmol 5-bromo indole, 0.1mmol [HMim] BF is added in 25ml round-bottomed flask 4ionic liquid and 0.5ml water, stirring reaction 9 hours when 60 DEG C.All the other steps are with embodiment 1, and obtain red brown solid N-((5-bromo-3-indyl)-phenyl) the methyl-N-methyl aniline 336.5mg that purity is 99%, isolated yield is 86.0%, and fusing point is 186-188 DEG C.
Infrared spectrogram IR (KBr) v:739,1506,1611,2927,3408cm -1.
Nuclear magnetic resonance data: 1h NMR (500MHz, CDCl 3): δ 2.81 (s, 3H), 5.53 (s, 1H), 6.56 (d, J=10.0Hz, 3H), 6.75-6.83 (m, 3H), 7.06 (d, J=8.0Hz, 2H), 7.27-7.33 (m, 5H), 7.53 (s, 1H), 8.01 (s, 1H); 13c NMR (125MHz, CDCl 3): δ 31.0,47.9,112.3,112.6,120.6,122.1,124.8,125.1,126.5,128.1,128.5,129.5,135.5,144.7,147.3.
Product is consistent with bibliographical information through qualification.
Embodiment 4, N-(synthesis of 3-indyl-(4-p-methoxy-phenyl) methyl-N-methyl aniline, structural formula is:
1.0mmol aubepine, 2mmol methylphenylamine, 1.0mmol indoles, 0.1mmol [HMim] BF is added in 25ml round-bottomed flask 4ionic liquid and 0.5ml water, stirring reaction 11 hours when 60 DEG C.All the other steps with embodiment 1, obtain purity be 99% red brown solid N-(3-indyl-(4-p-methoxy-phenyl) methyl-N-methyl aniline 257.5mg, isolated yield is 75.2%, and fusing point is 142-143 DEG C.
Infrared spectrogram IR (KBr) v:743,1027,1179,1454,1509,1613,2923,3043,3406cm -1.
Nuclear magnetic resonance data: 1h NMR (500MHz, CDCl 3): δ 2.79 (s, 3H), 3.75 (s, 3H), 5.51 (s, 1H), 6.52-6.58 (m, 2H), 6.81-6.86 (m, 3H), 6.97-7.05 (m, 3H), 7.15 (d, J=10.0,3H), 7.25-7.40 (m, 3H), 7.86 (s, 1H); 13c NMR (125MHz, CDCl 3): δ 30.9,47.9,55.2,111.0,112.3,113.5,119.6,119.7,121.8,123.6,123.8,127.1,129.7,129.8,133.0,136.9,147.6,157.8; IR (KBr):;
Product is consistent with bibliographical information through qualification.
Embodiment 5, [HMim] BF 4ionic liquid recycles synthesis N-(3-indyl-phenyl) methyl-N-methyl aniline
All concrete steps are with embodiment 1, and aqueous phase after drying afterwards, obtain [HMim] BF 4ionic liquid, obtain red brown solid N-(3-indyl-phenyl) the methyl-N-methyl aniline 278.0mg that purity is 99% when the 4th recycles, isolated yield is 89.0%.Product is consistent with bibliographical information through qualification.
Content disclosed according to the present invention, those skilled in the art can apply the present invention to greatest extent.Therefore, above-mentioned preferred specific embodiment only illustrates, but not limits the scope of the invention by any way.

Claims (5)

1., with aromatic aldehyde, indoles and the secondary amine method for Material synthesis 3-amine alkyl-indol, it is characterized in that aromatic aldehyde, methylphenylamine, indoles and catalyzer [HMim] BF 4ionic liquid adds in reaction flask simultaneously, and wherein aromatic aldehyde, methylphenylamine and indoles mol ratio are 1: 2: 1, and add a small amount of water, and stirring reaction 3-12 hour when 60 DEG C, obtains thick product.Crude by column chromatography obtains 3-amine alkyl-indol sterling after being separated
2. the synthetic method of 3-amine alkyl as claimed in claim 1, is characterized in that described indoles is the indoles of various replacement, its R 1for hydrogen, bromine, methoxyl group; Described aromatic aldehyde is the aromatic aldehyde of various replacement, its R 2for hydrogen or monosubstituted, polysubstituted halogen, alkoxyl group, hydroxyl or nitro.
3. the synthetic method of 3-amine alkyl as claimed in claim 1, is characterized in that described catalyzer [HMim] BF 4ionic liquid can be recycled.
4. the synthetic method of 3-amine alkyl as claimed in claim 1, is characterized in that described catalyzer [HMim] BF 4ionic liquid optimum amount is 10% of aromatic aldehyde molecular fraction.
5. the synthetic method of 3-amine alkyl as claimed in claim 1, is characterized in that described a small amount of water is distilled water.
CN201510011882.6A 2015-01-05 2015-01-05 [HMim] BF in water4Ionic liquid-catalyzed synthesis 3- amine alkyl-indol Expired - Fee Related CN104592089B (en)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20020198252A1 (en) * 2001-05-24 2002-12-26 Joseph Payack Process for the preparation of alkylamine substituted indoles
CN102234228A (en) * 2010-05-05 2011-11-09 北京石油化工学院 Method for synthesizing trimethylolpropane fatty acid ester under catalysis of ionic liquid
CN103342675A (en) * 2013-05-17 2013-10-09 安徽工业大学 Preparation method of diindolylmethane derivative through catalysis

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20020198252A1 (en) * 2001-05-24 2002-12-26 Joseph Payack Process for the preparation of alkylamine substituted indoles
CN102234228A (en) * 2010-05-05 2011-11-09 北京石油化工学院 Method for synthesizing trimethylolpropane fatty acid ester under catalysis of ionic liquid
CN103342675A (en) * 2013-05-17 2013-10-09 安徽工业大学 Preparation method of diindolylmethane derivative through catalysis

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
GOUTAM BRAHMACHARI，等: "One-Pot Synthesis of 3-[(N-Alkylanilino)(aryl)methyl]indoles via a Transition Metal Assisted Three-Component Condensation at Room Temperature", 《JOURNAL OF HETEROCYCLIC CHEMISTRY》 *
RAVINDRAN, ANASWARA，等: "One-pot synthesis of 3-substituted indole derivatives using moisture stable, reusable, and task specific ionic liquid catalysts", 《INDIAN JOURNAL OF CHEMISTRY, SECTION B: ORGANIC CHEMISTRY INCLUDING MEDICINAL CHEMISTRY》 *

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