CN105566235B - The method of the substep synthesis triazoles of NH 1,2,3 is catalyzed using aluminium salt - Google Patents

Abstract

The invention relates to a method for synthesizing NH-1,2,3-triazole step-by-step by using an aluminum salt catalyst, which belongs to the technical field of organic and pharmaceutical synthesis, and is characterized in that: under the catalysis of an aluminum salt catalyst, nitroolefin and alkene Sodium nitride undergoes 1,3-dipolar cycloaddition reaction, wherein the nitroalkene is aryl or aryl-substituted nitroalkene. The beneficial effects of the present invention are: the present invention uses cheap and easy-to-obtain AlCl ₃ , Al ₂ O ₃ or Al ₂ (SO ₄ ) ₃ as a catalyst, and aluminum ions activate the nitro group of nitroalkene, making the reaction easier in a mild Under conditions, the productive rate of reaction has been improved, and NH-1,2,3-triazole compound has been synthesized conveniently and effectively. Compared with existing methods, the reaction conditions of the present invention are mild, the reaction time section, safe It has good properties, simple operation, high reaction efficiency and low catalyst cost, which is a method with potential application value.

Description

Method for step-by-step synthesis of NH-1,2,3-triazoles catalyzed by aluminum salts

technical field

The invention relates to a method for synthesizing NH-1,2,3-triazole step by step by using aluminum salt catalysis, and belongs to the technical field of organic and pharmaceutical synthesis.

technical background

1,2,3-Triazole compounds are a class of nitrogen-containing heterocyclic compounds with important physiological activities, widely used in preservatives, pesticides, optical materials, dyes, HIV-1 inhibitors, antibiotics, selective β3-adrenoid Antagonists, antivirals and anticonvulsants. Activity testing shows that 4-aryl-NH-1,2,3-triazole compounds can be used as human methionine aminopeptidase inhibitors. Recent literature reports that some 4-aryl-NH-1,2,3-triazole compounds also have indoleamine 2,3-dioxygenase inhibitory activity and are potential IDO inhibitors, so NH-1, 2,3-triazole compounds can be used to treat various major human diseases such as cancer, Alzheimer's disease, and cataract, and have broad market prospects.

The early 1,3-dipolar Huisgen cycloaddition reaction of organic azides and terminal alkynes synthesized mixtures of 1,4-disubstituted and 1,5-disubstituted triazoles. This reaction requires a strong electron-withdrawing group attached to the azide compound or the alkynyl group as an activation group, and requires high temperature and pressure and a long reaction time. Therefore, the application of synthesizing 1,4-disubstituted-1,2,3-triazole compounds is greatly limited.

In 1971, Zefirow et al. reported a method for synthesizing 1H-1,2,3-triazole compounds using NaN ₃ and nitroalkenes or nitrile alkenes as raw materials and DMSO as a solvent. Although this type of reaction can be carried out at room temperature, olefins containing nitro or nitrile groups must be used as raw materials. The raw materials are not easy to obtain, the versatility of the reaction is limited, and the yield is low, only 10% to 60%. In 1994, Moltzen's group added aryne to TMSN ₃ and refluxed it for 72 hours under the protection of N ₂ . After washing with water to remove the silicon group, NH-1,2,3-triazole was obtained with a yield of 76%. In the absence of Cu(I) catalysis, the reaction requires higher temperature and prolonged reflux. In 2004, Kim's group reported that 4-(2-pyridyl)-NH-1,2,3-triazole was synthesized by refluxing 2-pyridylacetylene and TMSN ₃ in DMF, with a yield of 38%-71%. This method reaction temperature is higher, and productive rate is not high. In the same year, Yamamoto et al. reported the cycloaddition reaction between alkynes and TMSN ₃ under the catalysis of 5 mol% CuI. The synthesis method—DMF and MeOH (V:V=9:1) as the solvent, react at 100°C for 10 to 24 hours, and the yield of synthesizing 4-substituted-NH-1,2,3-triazole compounds can reach up to 95% . The disadvantage of this method is that the reaction temperature is higher and the time is longer. In 2006, Barluenga et al. proposed an effective method for the synthesis of 1H-1,2,3-triazole compounds using (E)-β-bromoarylene and NaN ₃ as raw materials. The method uses Pd ₂ (dba) ₃ -Xantphos is used as a catalyst, reacting in Dioxane or DMSO solvent for 14 to 24 hours, the conversion can be almost quantitatively completed. The disadvantage of this method is that the reaction will use expensive palladium series catalysts, and the reaction time is longer. In the same year, Weinreb et al. used a commercial 4-tolyl vinyl sulfone as a raw material to react with NaN ₃ in an acid-catalyzed MeOH system to synthesize a valuable intermediate β-4-methylstyrene Azide (TSE-N ₃ ). This intermediate affords a TSE-protected 1,2,3-triazole via Cu(I)-catalyzed 1,3-dipolar cycloaddition. Using KOBu-t in THF can remove the protecting group to obtain 4-substituted-1H-1,2,3-triazole with a yield of 61%-93%. The disadvantage of this method is that there are many synthetic steps and the reaction time is long. In 2007, Cheng's group synthesized a group of 4-aryl-5-nitrile-NH-1,2,3-triazoles by cycloaddition of homemade aryl alkyne nitriles with NaN ₃ with a yield of 50%. ~80%. The disadvantage of this method is that the reaction requires a higher temperature, and the substrate is difficult to synthesize. In 2008, Shi et al. reported a new synthetic route for the synthesis of 4,5-disubstituted-NH-1,2,3-triazoles by a _three -component reaction using nitroalkenes, NaN3, and aromatic aldehydes as raw materials. The reaction is catalyzed by L-proline, reacted in DMSO at room temperature for 8-10 hours, and the yield is generally 70%-90%.

In summary, the above methods for synthesizing NH-1,2,3-triazole compounds are all difficult to generate, long reaction time, high reaction temperature, low yield, few suitable substrates or difficult synthesis, high toxicity of raw materials or safety disadvantages such as poor performance and expensive catalysts.

Contents of the invention

In order to solve the deficiencies in the prior art, the object of the present invention is to provide a method for synthesizing NH-1,2,3-triazole in steps using aluminum salt catalysis with short reaction time, mild conditions, good safety and high yield .

In order to achieve the above object, the present invention is achieved through the following technical solutions: a method for synthesizing NH-1,2,3-triazoles step-by-step through the catalysis of an aluminum salt, characterized in that: under the catalysis of an aluminum salt catalyst, nitrate The 1,3-dipolar cycloaddition reaction between the base alkenes and sodium azide, wherein the nitroalkenes are aryl or aryl-substituted nitroalkenes.

According to the above scheme, the aluminum salt catalyst is selected from Al ₂ O ₃ , Al ₂ (SO ₄ ) ₃ or AlCl ₃ .

According to the above scheme, the aluminum salt catalyst is AlCl ₃ .

According to the above scheme, the molar dosage of the aluminum salt catalyst is 0.05-0.2 times that of the nitroolefin.

According to the above scheme, the molar dosage of the aluminum salt catalyst is 0.1 times that of the nitroolefin.

According to the above scheme, the solvent used is DMSO, acetonitrile, methanol, ethanol, toluene, chloroform or THF.

According to the above scheme, the solvent used was DMSO.

According to the above scheme, the reaction is carried out at a temperature in the range of 0-110°C.

According to the above scheme, the reaction was carried out at room temperature.

According to the above scheme, the reaction time is 1-1.5 hours.

The specific reaction formula involved in the present invention is shown in formula I:

The beneficial effects of the present invention are: the present invention uses cheap and easy-to-obtain AlCl ₃ , Al ₂ O ₃ or Al ₂ (SO ₄ ) ₃ as a catalyst, and aluminum ions activate the nitro group of nitroalkene, making the reaction easier in a mild Under conditions, the productive rate of the reaction is improved, and the NH-1,2,3-triazole compound is conveniently and effectively synthesized. Compared with the existing method, the reaction condition of the present invention is mild, the reaction time section is safe and It has good properties, simple operation, high reaction efficiency and low catalyst cost, which is a method with potential application value.

detailed description

In order to better understand the present invention, the content of the present invention is further illustrated below in conjunction with the examples, but the content of the present invention is not limited to the following examples.

Example 1:

Synthesis of 4-phenyl-2H-1,2,3-triazole:

The reaction formula is:

The specific steps are: add 0.33mmol nitrostyrene, 0.36mmol sodium azide, 0.03mmol AlCl ₃ , 2mL DMSO to a 50mL round-bottom flask, stir the reaction with magnetic force at room temperature for 1 hour, then extract the reaction with ethyl acetate solution, the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain the crude product, which was carried out with ethyl acetate/petroleum ether=1:5 (V/V) as the eluent The desired product was obtained by column separation and purification, and the product was a white solid with a yield of 94%.

The result of the proton nuclear magnetic spectrum of the product obtained is: ¹ H NMR (600MHz, DMSO-d ₆ ): δ8.32(s, 1H), 7.84(d, J=7.4Hz, 2H), 7.43(t, J=7.7 Hz,2H),7.33(t,J=7.4Hz,1H).

Example 2:

Synthesis of 4-phenyl-2H-1,2,3-triazole:

The reaction formula is:

The specific steps are: add 0.33mmol nitrostyrene, 0.36mmol sodium azide, 0.03mmol Al ₂ O ₃ , and 2mL DMSO to a 50mL round-bottomed flask, and react with magnetic stirring for 1 hour at room temperature. The reaction solution was extracted, the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain the crude product, which was rinsed with ethyl acetate/petroleum ether=1:5 (V/V) Liquid was subjected to column separation and purification to obtain the desired product, which was a white solid with a yield of 73%.

The result of the proton nuclear magnetic spectrum of the product obtained is: ¹ H NMR (600MHz, DMSO-d ₆ ): δ8.32(s, 1H), 7.84(d, J=7.4Hz, 2H), 7.43(t, J=7.7 Hz,2H),7.33(t,J=7.4Hz,1H).

Example 3:

Synthesis of 4-phenyl-2H-1,2,3-triazole:

The reaction formula is:

The specific steps are: add 0.33mmol nitrostyrene, 0.36mmol sodium azide, 0.03mmol Al ₂ (SO ₄ ) ₃ , and 2mL DMSO to a 50mL round-bottomed flask, stir and react with magnetic force for 1 hour at room temperature, then wash with acetic acid The reaction solution was extracted with ethyl ester, the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain the crude product, which was obtained with ethyl acetate/petroleum ether=1:5 (V/V) The eluent was subjected to column separation and purification to obtain the desired product, which was a white solid with a yield of 75%.

The result of the proton nuclear magnetic spectrum of the product obtained is: ¹ H NMR (600MHz, DMSO-d ₆ ): δ8.32(s, 1H), 7.84(d, J=7.4Hz, 2H), 7.43(t, J=7.7 Hz,2H),7.33(t,J=7.4Hz,1H).

Example 4:

Synthesis of 4-p-methylphenyl-2H-1,2,3-triazole:

The reaction formula is:

The specific steps are: add 0.33mmol nitro-p-methylstyrene, 0.36mmol sodium azide, 0.03mmolAlCl ₃ , and 2mL DMSO to a 50mL round-bottomed flask, and react with magnetic stirring for 1 hour at room temperature. The reaction solution was extracted, the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain the crude product, which was rinsed with ethyl acetate/petroleum ether=1:5 (V/V) Liquid was subjected to column separation and purification to obtain the desired product, which was a white solid with a yield of 90%.

The result of the proton nuclear magnetic spectrum of the product obtained is: ¹ H NMR (600MHz, DMSO-d6): δ8.25(s, 1H), 7.72(d, J=8.1Hz, 2H), 7.24(d, J=7.9Hz ,2H),2.31(s,3H).

Example 5:

Synthesis of 4-(2,4-dichlorophenyl)-2H-1,2,3-triazole:

The reaction formula is:

The specific steps are: add 0.33mmol of nitro 2,4-dichlorophenylethylene, 0.36mmol of sodium azide, 0.03mmol of AlCl ₃ , and 2mL of DMSO into a 50mL round-bottomed flask, and react with magnetic stirring for 1 hour at room temperature. The reaction solution was extracted with ethyl acetate, the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain the crude product, which was prepared with ethyl acetate/petroleum ether=1:5 (V/V ) for the eluent to carry out column separation and purification to obtain the desired product, the product is a white solid, and the yield is 95%.

The result of the proton nuclear magnetic spectrum of the product obtained is: ¹ H NMR (600MHz, DMSO-d ₆ ): δ8.38(s, 1H), 7.94(d, J=8.4Hz, 1H), 7.72(d, J=1.8 Hz,1H),7.51(q,J=8.4,2.1Hz,1H).

Embodiment 6:

Synthesis of 4-o-nitrophenyl-2H-1,2,3-triazole:

The reaction formula is:

The specific steps are: add 0.33mmol of nitro-o-nitrophenylethylene, 0.36mmol of sodium azide, 0.03mmol of AlCl ₃ , and 2mL of DMSO into a 50mL round-bottom flask; The ester extraction reaction solution, the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain the crude product, which was rinsed with ethyl acetate/petroleum ether=1:5 (V/V) The washing solution was subjected to column separation and purification to obtain the desired product, which was a white solid with a yield of 85%.

The result of the proton nuclear magnetic spectrum of the obtained product is: ¹ H NMR (600MHz, DMSO-d ₆ ): δ8.24(s, 1H), 7.89(s, 1H), 7.81(d, J=7.2Hz, 1H), 7.76–7.68(m,1H),7.64–7.54(m,1H).

Embodiment 7:

Synthesis of 4-o-bromophenyl-2H-1,2,3-triazole:

The reaction formula is:

The specific steps are: add 0.33mmol of nitro-o-bromophenylethylene, 0.36mmol of sodium azide, 0.03mmol of AlCl ₃ , and 2mL of DMSO into a 50mL round-bottomed flask, and react with magnetic stirring for 1 hour at room temperature. The reaction solution was extracted, the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain the crude product, which was rinsed with ethyl acetate/petroleum ether=1:5 (V/V) Liquid was subjected to column separation and purification to obtain the desired product, which was a white solid with a yield of 95%.

The result of the proton nuclear magnetic spectrum of the product obtained is: ¹ H NMR (600MHz, CDCl ₃ ): δ8.27(s, 1H), 7.81(d, J=6.1Hz, 1H), 7.68(q, J=8.1,0.9 Hz,1H),7.39(m,J=7.6,1.0Hz,1H),7.24(m,J=7.9,1.7Hz,1H).

Embodiment 8:

Synthesis of 4-o-chlorophenyl-2H-1,2,3-triazole:

The reaction formula is:

The specific steps are: add 0.33mmol of nitro-o-chlorophenylethylene, 0.36mmol of sodium azide, 0.03mmol of AlCl ₃ , and 2mL of DMSO into a 50mL round-bottom flask; The reaction solution was extracted, the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain the crude product, which was rinsed with ethyl acetate/petroleum ether=1:5 (V/V) Liquid was subjected to column separation and purification to obtain the desired product, which was a white solid with a yield of 90%.

The result of the proton nuclear magnetic spectrum of the product obtained is: ¹ H NMR (600MHz, DMSO-d6): δ8.33(s, 1H), 7.89(s, 1H), 7.55(d, J=7.9Hz, 1H), 7.44 –7.40(m,1H),7.38(td,J=7.7,1.5Hz,1H).

Embodiment 9:

Synthesis of 4-3-furan-2H-1,2,3-triazole:

The reaction formula is:

The specific steps are: add 0.33mmol 2-furylnitroethylene, 0.36mmol sodium azide, 0.03mmol AlCl ₃ , and 2mL DMSO to a 50mL round-bottomed flask, stir and react with magnetic force for 1 hour at room temperature, then extract with ethyl acetate The reaction solution, the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain the crude product. The crude product was eluent with ethyl acetate/petroleum ether=1:5 (V/V) Column separation and purification were performed to obtain the desired product as a white solid with a yield of 90%.

The result of the proton nuclear magnetic spectrum of the product obtained is: ¹ H NMR (600MHz, CDCl ₃ ): δ7.97(s, 1H), 7.51(d, J=1.2Hz, 1H), 6.85(d, J=3.3Hz, 1H),6.51(m.1H).

Example 10:

Synthesis of 4-2-pyridyl-2H-1,2,3-triazole:

The reaction formula is:

The specific steps are: add 0.33mmol 2-pyridylnitroethylene, 0.36mmol sodium azide, 0.03mmolAlCl ₃ , 2mL DMSO to a 50mL round-bottomed flask, and react with magnetic stirring for 1 hour at room temperature. The reaction solution was extracted, the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain the crude product, which was rinsed with ethyl acetate/petroleum ether=1:5 (V/V) Liquid was subjected to column separation and purification to obtain the desired product, which was a white solid with a yield of 82%.

The result of the proton nuclear magnetic spectrum of the product obtained is: 1H NMR (400MHz, CDCl3) δ8.72 (d, J=4.5Hz, 1H), 8.34 (s, 1H), 8.00 (d, J=7.1Hz, 1H), 7.82(t,J=7.5Hz,1H),7.35–7.28(m,1H).

The present invention adopts cheap and easy-to _- get AlCl3 as a catalyst to catalyze the reaction of nitroolefins and sodium azide, and conveniently and effectively synthesize NH-1,2,3-triazole compounds. Compared with existing methods, The invention has mild reaction conditions, short reaction time, good safety, convenient operation, high reaction efficiency and low catalyst, and is a method with potential application value.

The above-mentioned embodiments do not limit the present invention in any form, and all technical solutions obtained by means of equivalent replacement or small transformation fall within the protection scope of the present invention.

Claims (8)

1. catalyze and synthesize NH-1, the method for 2,3- triazoles using aluminium salt, it is characterised in that：In aluminium salt catalyst AlCl₃Catalysis Under, with sodium azide 1,3- Dipolar Cycloadditions occur for nitroolefin, and wherein nitroolefin is the nitre of aryl or substituted aryl Base alkene.

2. method according to claim 1, it is characterised in that：Aluminium salt catalyst mole dosage is nitroolefin dosage 0.05-0.2 times.

3. method according to claim 2, it is characterised in that：Aluminium salt catalyst mole dosage is the 0.1 of nitroolefin dosage Times.

4. method according to claim 1, it is characterised in that：Solvent for use is DMSO, acetonitrile, methanol, ethanol, toluene, three Chloromethanes or THF.

5. method according to claim 4, it is characterised in that：Solvent for use is DMSO.

6. method according to claim 4, it is characterised in that：Reaction is carried out within the temperature range of 0-110 DEG C.

7. method according to claim 6, it is characterised in that：Reaction is carried out at ambient temperature.

8. method according to claim 6, it is characterised in that：Reaction time is 1-1.5 hours.