阅读说明：本技术 一种乙炔基苯胺的制备方法 (Preparation method of ethynylaniline ) 是由 林霞 肖孝辉 方成涛 罗虹 于 2020-12-21 设计创作，主要内容包括：本发明公开了一种乙炔基苯胺的制备方法,包括如下步骤：硝基乙苯为原料,以MBr-MBrO-3-H-2SO-4(M＝Na or K)为溴化试剂,通过自由基溴代反应制备得到1,1-二溴-1-(硝基苯基)乙烷,再在碱的作用下进行消除反应得到硝基苯乙炔,最后通过Fe/HCl还原得到乙炔基苯胺。本发明的制备方法具有原料价廉易得、操作简单安全、反应选择性好、产品收率高、三废排放少等优点。(The invention discloses a preparation method of ethynylaniline, which comprises the following steps: nitroethylbenzene as raw material, MBr-MBrO 3 ‑H 2 SO 4 (M ═ Na or K) is a brominating reagent, 1-dibromo-1- (nitrophenyl) ethane is prepared through free radical bromination reaction, elimination reaction is carried out under the action of alkali to obtain nitrobenzene acetylene, and finally, ethynylaniline is obtained through reduction of Fe/HCl. The preparation method has the advantages of cheap and easily obtained raw materials, simple and safe operation, good reaction selectivity, high product yield, less three-waste discharge and the like.)

1. The preparation method of the ethynylaniline is characterized by comprising the following steps:

(1) using nitroethylbenzene 1 as raw material and MBr-MBrO₃-H₂SO₄Preparing 1, 1-dibromo-1- (nitrophenyl) ethane 2 by using a free radical bromination reaction as a bromination reagent;

(2) then carrying out elimination reaction under the action of alkali to obtain nitrobenzene acetylene 3;

(3) finally, obtaining ethynylaniline 4 through Fe/HCl reduction;

the reaction route is as follows:

wherein, MBr-MBrO₃-H₂SO₄M of (A) is Na or K.

2. The preparation method according to claim 1, wherein the specific steps of step (1) are as follows: adding an organic solvent S1, nitroethylbenzene 1, bromate, bromide and water into a reaction bottle provided with a stirring and refluxing condenser pipe and a thermometer, stirring and heating to a refluxing temperature, dropwise adding an initiator solution and sulfuric acid, and tracking the reaction process by a thin layer chromatography; after the reaction is finished, cooling to room temperature, adding a proper amount of saturated sodium bisulfite solution, reacting for 5 minutes, separating, extracting the water phase with an organic solvent S1, separating, combining the organic phases, drying with anhydrous sodium sulfate, filtering, and concentrating the filtrate under reduced pressure to obtain light yellow solid 1, 1-dibromo-1- (nitrophenyl) ethane 2.

3. The preparation method according to claim 2, wherein the organic solvent S1 is one or more of dichloromethane, 1, 2-dichloroethane, and carbon tetrachloride; the bromide is one or a mixture of two of sodium bromide and potassium bromide; the bromate is one or a mixture of two of sodium bromate and potassium bromate; the initiator is one or a mixture of more of azodiisoheptonitrile, azodiisobutyronitrile and dibenzoyl peroxide.

4. The method according to claim 2, wherein the amount ratio of the substance of nitroethylbenzene, bromate, bromide and concentrated sulfuric acid is 1: 0.67 to 0.69: 1.33 to 1.41: 1 to 1.06; the dosage of the organic solvent S1 is 0.5-1 mL/mmol based on the substance of nitroethylbenzene; the dosage of the initiator is 2.5-5 mg/mmol based on the substance of the nitroethylbenzene; the dosage of the water is 0.01-0.2 mL/mmol based on the substance of the nitroethylbenzene.

5. The preparation method according to claim 1, wherein the specific steps of step (2) are as follows: at room temperature, adding an organic solvent S2 and alkali into a reaction bottle, uniformly stirring and dispersing, adding the light yellow solid 1, 1-dibromo-1- (nitrophenyl) ethane 2 obtained in the step (2), stirring and heating to 40-60 ℃, and tracking the reaction process by using a thin layer chromatography; after the reaction is finished, cooling to room temperature, filtering, recovering bromide, decompressing and concentrating the filtrate to obtain a crude product, and purifying the crude product by column chromatography to obtain the nitrobenzene acetylene 3.

6. The preparation method according to claim 5, wherein the organic solvent S2 is one or more of methanol, ethanol, propanol, isopropanol and tert-butanol; the alkali is one or a mixture of more of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium methoxide, sodium ethoxide and potassium tert-butoxide.

7. The method according to claim 5, wherein the mass ratio of 1, 1-dibromo-1- (nitrophenyl) ethane 2 to the base is 1:2 to 2.5; the amount of the organic solvent S2 is 1-4 mL/mmol based on the amount of the 1, 1-dibromo-1- (nitrophenyl) ethane 2 substance.

8. The preparation method according to claim 1, wherein the specific steps of step (3) are as follows: adding water and iron powder into a reaction bottle at room temperature, dropwise adding a proper amount of concentrated hydrochloric acid while stirring, dropwise adding a methanol solution of nitrobenzene acetylene 3, heating for reflux reaction after dropwise adding, and tracking the reaction process by a thin-layer chromatography; after the reaction is finished, cooling to room temperature and filtering; concentrating the filtrate under reduced pressure to recover methanol, extracting the residual water phase after recovering methanol with appropriate amount of ethyl acetate for 3 times, combining the organic phases, drying with anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure, and purifying the crude product by column chromatography to obtain ethynylaniline 4.

9. The method according to claim 8, wherein the mass ratio of the nitrobenzene acetylene 3 to the iron powder is 1:1 to 4; the dosage of the methanol is 1-4 mL/mmol based on the substance of the nitrobenzene acetylene 3; the amount of the water is 1-4 mL/mmol based on the substance of the nitrobenzene acetylene 3.

Technical Field

The invention belongs to the field of organic chemistry, and particularly relates to a preparation method of ethynylaniline.

Background

The ethynylaniline aromatic ring is connected with two important functional groups of amino and carbon-carbon triple bond, and is a common organic synthesis intermediate. Such as: 3-ethynylaniline is a key intermediate of small molecule targeted drugs erlotinib hydrochloride and erlotinib hydrochloride for treating lung cancer; 4-ethynylaniline is a common raw material of functional polymer compounds, luminescent materials and the like.

The preparation methods of ethynylaniline reported in the literature at present can be roughly divided into the following four types:

1) coupling reaction of halogenated squarylamine and acetylene derivative under metal catalysis; such as (Organic Letters, 2001, 3(7), 993-:

2) desiliconizing the silicon derivative of aminophenylacetylene; such as (RSC Advances 2016, 6(95), 92845-:

3) 2-methyl-3- (aminophenyl) -3-butyn-2-ol degradation reaction; such as (Organic Letters, 2013, 15(3), 492-495; Acta Chemica Scandinavia, Series B: Organic Chemistry and Biochemistry, 1988, B42(7), 448-54):

4) elimination reaction of amino styrene derivative; such as (Tetrahedron Letters, 2011, 52(9), 992-:

5) reduction reaction of nitrobenzene acetylene; such as (Green Chemistry, 2014, 16(3), 1082-1086; Catalysis Communications, 2018, 103, 47-50):

the coupling reaction needs to use a noble metal catalyst, and aminophenylacetylene derivatives are not easy to obtain and the raw materials are expensive, so the method for preparing ethynylaniline by reducing nitrophenylacetylene is still a commonly used method at present, and the methods for preparing the ethynylaniline by reducing the nitrophenylacetylene at present mainly comprise the following types:

1) coupling reaction of halogenated nitrobenzene and acetylene derivative under metal catalysis; such as (Organic Letters, 2018, 20(15), 4601-:

2) 2-methyl-3- (nitrophenyl) -3-butyn-2-ol degradation reaction; such as (Langmuir, 2009, 25(19), 11796-:

3) desilication reaction of silicon derivatives of nitrobenzene acetylene; for example (Organic Letters,16(18),4948 + 4951; 2014; Tetrahedron,71(22),3619 + 3624; 2015):

4) condensation reaction of nitrobenzaldehyde with (1-diazo-2-oxo-propanol) -dimethyl phosphonate: such as (European Journal of Medicinal Chemistry, 2016, 122, 436-:

5) elimination reaction of nitrostyrene derivatives: such as (Advanced Synthesis & Catalysis, 2015, 357(2-3), 553-) -560; Organic & Biomolecular Chemistry, 2017, 15(47), 9979-:

6) dehydration reaction of nitroacetophenone; such as (proceedings of Chengdu university of science and technology, 1986, 4, 21-6; Synlett, 2009, 4, 558-:

7) decarboxylation elimination of 2, 3-dibromo-3- (nitrophenyl) propionic acid: such as (Chinese Journal of Chemistry, 2011, 29(11), 2350-:

although the preparation methods of the nitrobenzene acetylene reported in the literature are more, various adverse factors such as noble metal catalysis and difficulty in obtaining raw materials exist, so that the production cost of the ethynylaniline is higher, and the production cost of downstream medicines and materials is influenced.

The invention aims to develop a preparation method of ethynyl squaramine, which has the advantages of simple and safe operation, cheap and easily obtained raw materials, low production cost, less three-waste discharge and easy industrialization.

Disclosure of Invention

In order to overcome the defects in the prior art, the invention provides the preparation method of the ethynylaniline, which has the advantages of cheap and easily obtained raw materials, simple and safe operation, good reaction selectivity, high product yield, less discharge of three wastes and the like.

The preparation method of the ethynylaniline is characterized by comprising the following steps:

(1) using nitroethylbenzene 1 as raw material and MBr-MBrO₃-H₂SO₄Preparing 1, 1-dibromo-1- (nitrophenyl) ethane 2 by using a free radical bromination reaction as a bromination reagent;

(2) then carrying out elimination reaction under the action of alkali to obtain nitrobenzene acetylene 3;

(3) finally, obtaining ethynylaniline 4 through Fe/HCl reduction;

the reaction route is as follows:

wherein, MBr-MBrO₃-H₂SO₄M of (A) is Na or K.

Further, the specific steps of the step (1) are as follows: adding an organic solvent S1, nitroethylbenzene 1, bromate, bromide and water into a reaction bottle provided with a stirring and refluxing condenser pipe and a thermometer, stirring and heating to a refluxing temperature, dropwise adding an initiator solution and sulfuric acid, and tracking the reaction process by a thin layer chromatography; after the reaction is finished, cooling to room temperature, adding a proper amount of saturated sodium bisulfite solution, reacting for 5 minutes, separating, extracting the water phase with an organic solvent S1, separating, combining the organic phases, drying with anhydrous sodium sulfate, filtering, and concentrating the filtrate under reduced pressure to obtain light yellow solid 1, 1-dibromo-1- (nitrophenyl) ethane 2.

The organic solvent S1 can be one or a mixture of more of dichloromethane, 1, 2-dichloroethane and carbon tetrachloride, and most preferably 1, 2-dichloroethane; the bromide can be one or a mixture of two of sodium bromide and potassium bromide, and is most preferably sodium bromide; the bromate can be one or a mixture of two of sodium bromate and potassium bromate, and sodium bromate is most preferable; the initiator is one or a mixture of several of azodiisobutyronitrile, azodiisobutyronitrile and dibenzoyl peroxide, and most preferably azodiisobutyronitrile.

The mass ratio of the nitroethylbenzene, the bromate, the bromide and the concentrated sulfuric acid is 1: 0.67-0.69: 1.33-1.41: 1-1.06, and the more preferable ratio is 1:0.69:1.37: 1.03; the dosage of the organic solvent S1 is 0.5-1 mL/mmol, preferably 0.76-1 mL/mmol, based on the substance of nitroethylbenzene; the dosage of the initiator is 2.5-5 mg/mmol, preferably 3.5-4 mg/mmol, based on the substance amount of the nitroethylbenzene; the dosage of the water is 0.01-0.2 mL/mmol, preferably 0.05-0.1 mL/mmol, based on the substance amount of the nitroethylbenzene.

Further, the specific steps of the step (2) are as follows: at room temperature, adding an organic solvent S2 and alkali into a reaction bottle, uniformly stirring and dispersing, adding the light yellow solid 1, 1-dibromo-1- (nitrophenyl) ethane 2 obtained in the step (2), stirring and heating to 40-60 ℃, and tracking the reaction process by using a thin layer chromatography; after the reaction is finished, cooling to room temperature, filtering, recovering bromide, decompressing and concentrating the filtrate to obtain a crude product, and purifying the crude product by column chromatography to obtain the nitrobenzene acetylene 3.

The organic solvent S2 is one or a mixture of several of methanol, ethanol, propanol, isopropanol and tert-butanol, and ethanol is the most preferable; the alkali is one or a mixture of more of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium methoxide, sodium ethoxide and potassium tert-butoxide, and the most preferable is sodium hydroxide.

The mass ratio of 1, 1-dibromo-1- (nitrophenyl) ethane 2 to the base is 1:2 to 2.5, preferably 1: 2.1; the amount of the organic solvent S2 is 1 to 4mL/mmol, preferably 2 to 3mL/mmol, based on the amount of the 1, 1-dibromo-1- (nitrophenyl) ethane 2 substance.

Further, the specific steps of step (3) are: adding water and iron powder into a reaction bottle at room temperature, dropwise adding a proper amount of concentrated hydrochloric acid while stirring, dropwise adding a methanol solution of nitrobenzene acetylene 3, heating for reflux reaction after dropwise adding, and tracking the reaction process by a thin-layer chromatography; after the reaction is finished, cooling to room temperature and filtering; concentrating the filtrate under reduced pressure to recover methanol, extracting the residual water phase after recovering methanol with appropriate amount of ethyl acetate for 3 times, combining the organic phases, drying with anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure, and purifying the crude product by column chromatography to obtain ethynylaniline 4.

The mass ratio of the nitrobenzene acetylene 3 to the iron powder is 1: 1-4, preferably 1: 2-3; the dosage of the methanol is 1-4 mL/mmol, preferably 2-3 mL/mmol, based on the substance of the nitrobenzene acetylene 3; the amount of the water is 1-4 mL/mmol, preferably 2-3 mL/mmol, based on the amount of the nitrobenzene acetylene 3.

Compared with the prior art, the method prepares the ethynylaniline through three steps of free radical bromination reaction, elimination reaction and reduction reaction, and has the advantages that:

(1) all the raw materials are cheap and easy to obtain, and the use is safe.

(2) During bromination reaction, NaBr-NaBrO is selected₃/H₂SO₄The catalyst is a brominating reagent, has mild reaction conditions, can regulate and control the reaction process through the addition of sulfuric acid, controls the reaction selectivity and ensures that a target product is obtained with high yield; bromate and bromide are relatively stable solid substances, are easy to measure and are safe to use; the sodium sulfate formed as a by-product in the reaction is insoluble in organic solvents and can be easily separated from the product.

(3)1, 1-dibromo-1- (3-nitrophenyl) ethane is eliminated under the action of alkali to obtain nitrobenzene acetylene and bromide, the bromide is insoluble in an alcohol solvent, a product and the bromide can be separated by simple filtration, and the obtained bromide is recovered and can be used as a raw material for a first bromination reaction. The method can not only reduce the production cost, but also reduce the discharge of waste and protect the environment.

(4) The adopted reactions are classical organic chemical reactions, precious metal catalysis is not needed, the reaction selectivity is good, and the product yield is high; the reaction condition is mild, the operation is simple and safe, the required equipment is simple, and the investment is low; easy realization of recycling of byproducts, less discharge of three wastes, low production cost and good industrialization prospect

The method has the advantages of simple three-step reaction, cheap and easily obtained raw materials, simple, convenient and safe operation, simplified production process, reduced production cost, obviously improved yield of the aminophenylacetylene (4), high total yield of the three steps up to 78 percent, and suitability for industrial production.

Detailed Description

The substantial and significant advantages of the present invention are further illustrated below by the examples, without limiting the scope of the invention thereto.

Example 1

At 100mAn L flask was charged with 6.05g (40mmoL) of 3-nitroethylbenzene, 4.04g (26.8mmoL) of sodium bromate, 5.47g (53.2mmoL) of sodium bromide, 35mL of dichloroethane and 3mL of water in this order, charged into a reaction flask equipped with a stirrer, reflux condenser and thermometer, heating to reflux, rapidly adding 1/3 volumes of initiator solution (0.15g of azobisisobutyronitrile dissolved by 5mL of dichloroethane), after vigorous reflux of the system, slowly adding 3.92g of sulfuric acid (obtained by diluting 40mmoL of concentrated sulfuric acid with 1mL of water) and the rest of initiator solution dropwise, tracking by thin layer chromatography, cooling to room temperature after the reaction is finished, adding 10mL of saturated sodium bisulfite solution, reacting for 5 minutes, separating, extracting the water phase for 3 times (3x10mL) by dichloroethane, combining the organic phases, drying by anhydrous sodium sulfate, filtering, and concentrating the filtrate under reduced pressure to obtain a light yellow solid which is a crude product of 1, 1-dibromo-1- (3-nitrophenyl) ethane.¹H NMR(600MHz,CDCl₃)δ8.58(s,1H),8.18(ddd,J＝11.8,8.5,0.8Hz,2H),7.58(t,J＝8.1Hz,1H),3.02(s,3H)；¹³C NMR(151MHz,CDCl₃)δ148.1147.6,132.7,129.4,123.8,120.4,58.4,40.7.。

At room temperature, 50mL of absolute ethyl alcohol and 2.59g (64.8mmoL) of sodium hydroxide are added into a 100mL three-necked flask, the mixture is uniformly stirred, the crude product of the 1, 1-dibromo-1- (3-nitrophenyl) ethane obtained by bromination reaction is added in batches, the temperature is raised to 40-60 ℃ by stirring, and the reaction process is tracked by thin layer chromatography. After the reaction, filtration was carried out, the solid was recovered and reused, the filtrate was concentrated under reduced pressure, and the crude product was purified by column chromatography (the elution solvent was ethyl acetate: petroleum ether: 1:60 by volume) to obtain 4.43g of a reddish brown liquid which was 3-nitrophenylacetylene, with a yield of 75.3% in two steps.¹H NMR(600MHz,CDCl₃)δ8.30–8.28(m,1H),8.19–8.16(m,1H),7.77(d,J＝7.7Hz,1H),7.50(t,J＝8.0Hz,1H),3.22(s,1H)；¹³C NMR(151MHz,CDCl₃)δ147.9,137.7,129.3,126.8,123.8,123.4,81.0,79.8.。

At room temperature, 30mL of water and 5.04g (90mmoL) of iron powder are added into a reaction bottle, 0.15mL of concentrated hydrochloric acid is dropwise added while stirring, a 3-nitrophenylacetylene methanol solution (a solution obtained by dissolving 4.43g of 30mmoL of 3-nitrophenylacetylene in 30mL of methanol) is dropwise added, after the dropwise addition is finished, the heating reflux reaction is carried out, and the reaction progress is tracked by a thin layer chromatography. After the reaction is finished, cooling to room temperatureThe residue was removed by filtration, the filtrate was concentrated under reduced pressure to recover methanol, the residual aqueous phase was extracted 3 times (3 × 15mL) with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the crude product was purified by column chromatography (the eluting solvent was ethyl acetate: petroleum ether: 1:5 by volume) to give 3.27g of a reddish brown liquid which was 3-ethynylaniline, yield 92%.¹H NMR(600MHz,CDCl₃)δ7.10(t,J＝7.8Hz,1H),6.92–6.89(m,1H),6.82–6.80(m,1H),6.67(ddd,J＝8.1,2.4,0.9Hz,1H),3.62(s,2H),3.03(s,1H)；¹³C NMR(151MHz,CDCl₃)δ146.1,129.2,122.6,122.4,118.2,115.7,83.8,76.4.。

Example 2

6.05g (40mmoL) of 3-nitroethylbenzene, 4.16g (27.6mmoL) of sodium bromate, 5.64g (54.8mmoL) of sodium bromide, 35mL of dichloroethane and 3mL of water are sequentially added into a 100mL flask, the flask is provided with a stirring and refluxing condenser and a thermometer, the flask is heated to reflux, 1/3 volumes of initiator solution (obtained by dissolving 0.15g of azobisisobutyronitrile in 5mL of dichloroethane) are rapidly added, after violent reflux of the system occurs, 4.04g of sulfuric acid (obtained by diluting 41.2mmoL concentrated sulfuric acid with 1mL of water) and the rest of initiator solution are slowly added, the flask is tracked by thin layer chromatography, the temperature is reduced to room temperature after the reaction is finished, 10mL of saturated sodium bisulfite solution is added for reaction for 5 minutes, liquid separation is carried out, the aqueous phase is extracted for 3 times by dichloroethane (3x10mL), the organic phases are combined, anhydrous sodium sulfate is dried, filtered and the filtrate is concentrated under reduced pressure to obtain light yellow solid, the filtrate is 1, 1-dibromo-1- (3-nitrophenyl) ethane crude product.

At room temperature, 50mL of absolute ethyl alcohol and 2.89g (72.3mmoL) of sodium hydroxide are added into a 100mL three-necked flask, the mixture is uniformly stirred, the crude product of the 1, 1-dibromo-1- (3-nitrophenyl) ethane obtained by bromination reaction is added in batches, the temperature is raised to 40-60 ℃ by stirring, and the reaction process is tracked by thin layer chromatography. After the reaction, filtration was carried out, the solid was recovered and reused, the filtrate was concentrated under reduced pressure, and the crude product was purified by column chromatography (the elution solvent was ethyl acetate: petroleum ether: 1:60 by volume) to obtain 4.7g of a reddish brown liquid which was 3-nitrophenylacetylene, with a yield of 80% in two steps.

At room temperature, 30mL of water and 3.58g (64mmoL) of iron powder are added into a reaction bottle, 0.2mL of concentrated hydrochloric acid is dropwise added while stirring, a 3-nitrophenylacetylene methanol solution (a solution obtained by dissolving 4.7g of 32mmoL 3-nitrophenylacetylene in 30mL of methanol) is dropwise added, after the dropwise addition is finished, the heating reflux reaction is carried out, and the reaction progress is tracked by a thin layer chromatography. After the reaction, the reaction mixture was cooled to room temperature, the residue was filtered off, the filtrate was concentrated under reduced pressure to recover methanol, the residual aqueous phase was extracted 3 times (3 × 15mL) with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the crude product was purified by column chromatography (elution solvent was ethyl acetate: petroleum ether ═ 1:5, volume ratio) to obtain 3.48g of reddish brown liquid which was 3-ethynylaniline, yield 93.5%. .

Example 3

6.05g (40mmoL) of 3-nitroethylbenzene, 4.16g (27.6mmoL) of sodium bromate, 5.64g (54.8mmoL) of sodium bromide, 35mL of dichloroethane and 3mL of water are sequentially added into a 100mL flask, the flask is provided with a stirring and refluxing condenser and a thermometer, the flask is heated to reflux, 1/3 volumes of initiator solution (obtained by dissolving 0.15g of azobisisobutyronitrile in 5mL of dichloroethane) are rapidly added, after violent reflux of the system occurs, 4.04g of sulfuric acid (obtained by diluting 41.2mmoL concentrated sulfuric acid with 1mL of water) and the rest of initiator solution are slowly added, the flask is tracked by thin layer chromatography, the temperature is reduced to room temperature after the reaction is finished, 10mL of saturated sodium bisulfite solution is added for reaction for 5 minutes, liquid separation is carried out, the aqueous phase is extracted for 3 times by dichloroethane (3x10mL), the organic phases are combined, anhydrous sodium sulfate is dried, filtered and the filtrate is concentrated under reduced pressure to obtain light yellow solid, the filtrate is 1, 1-dibromo-1- (3-nitrophenyl) ethane crude product.

At room temperature, 50mL of absolute ethyl alcohol and 2.96g (74mmoL) of sodium hydroxide are added into a 100mL three-necked flask, the mixture is uniformly stirred, the crude product of the 1, 1-dibromo-1- (3-nitrophenyl) ethane obtained by bromination reaction is added in batches, the temperature is raised to 40-60 ℃ by stirring, and the reaction process is tracked by thin-layer chromatography. After the reaction, filtration was carried out, the solid was recovered and reused, the filtrate was concentrated under reduced pressure, and the crude product was purified by column chromatography (the elution solvent was ethyl acetate: petroleum ether: 1:60 by volume) to obtain 4.82g of a reddish brown liquid which was 3-nitrophenylacetylene, with a yield of 82% in the two steps.

At room temperature, 30mL of water and 3.7g (66mmoL) of iron powder are added into a reaction bottle, 0.2mL of concentrated hydrochloric acid is dropwise added under stirring, a 3-nitrophenylacetylene methanol solution (a solution obtained by dissolving 4.82g of 32.8mmoL of 3-nitrophenylacetylene in 30mL of methanol) is dropwise added, after the dropwise addition is finished, a heating reflux reaction is carried out, and the reaction process is tracked by a thin layer chromatography. After the reaction was completed, the reaction mixture was cooled to room temperature, the residue was filtered off, the filtrate was concentrated under reduced pressure to recover methanol, the residual aqueous phase was extracted 3 times (3 × 15mL) with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the crude product was purified by column chromatography (the elution solvent was ethyl acetate: petroleum ether ═ 1:5, volume ratio) to obtain 3.56g of reddish brown liquid which was 3-ethynylaniline, yield 92%.

Example 4

6.05g (40mmoL) of 3-nitroethylbenzene, 4.16g (27.6mmoL) of sodium bromate, 5.64g (54.8mmoL) of sodium bromide, 35mL of dichloroethane and 3mL of water are sequentially added into a 100mL flask, the flask is provided with a stirring and refluxing condenser and a thermometer, the flask is heated to reflux, 1/3 volumes of initiator solution (obtained by dissolving 0.15g of benzoyl peroxide with 5mL of dichloroethane) is rapidly added, after violent reflux of the system appears, 4.04g of sulfuric acid (obtained by diluting 41.2mmoL of concentrated sulfuric acid with 1mL of water) and the rest of initiator solution are slowly added dropwise, the flask is tracked by thin layer chromatography, the temperature is reduced to room temperature after the reaction is finished, 10mL of saturated sodium bisulfite solution is added for reaction for 5 minutes, liquid separation is carried out, the aqueous phase is extracted for 3 times with dichloroethane (3x10mL), the organic phases are combined, anhydrous sodium sulfate is dried, filtered, the filtrate is concentrated under reduced pressure to obtain light yellow solid which is 1, 1-dibromo-1- (3-nitrophenyl) ethane crude product.

At room temperature, 50mL of absolute ethyl alcohol and 2.72g (68mmoL) of sodium hydroxide are added into a 100mL three-necked flask, the mixture is uniformly stirred, the crude product of the 1, 1-dibromo-1- (3-nitrophenyl) ethane obtained by bromination reaction is added in batches, the mixture is stirred and heated to 40-60 ℃, and the reaction process is tracked by thin-layer chromatography. After the reaction, filtration was carried out, the solid was recovered and reused, the filtrate was concentrated under reduced pressure, and the crude product was purified by column chromatography (the elution solvent was ethyl acetate: petroleum ether: 1:60 by volume) to obtain 4.47g of a reddish brown liquid which was 3-nitrophenylacetylene, with a yield of 76% in the two steps.

At room temperature, 15mL of water and 3.41g (60.8mmoL) of iron powder are added into a reaction bottle, 0.2mL of concentrated hydrochloric acid is dropwise added under stirring, a 3-nitrophenylacetylene methanol solution (4.47g, a solution obtained by dissolving 30.4mmoL of 3-nitrophenylacetylene in 15mL of methanol) is dropwise added, and after the dropwise addition is completed, heating reflux reaction is carried out, and the reaction process is tracked by a thin layer chromatography. After the reaction was completed, the reaction mixture was cooled to room temperature, the residue was filtered off, the filtrate was concentrated under reduced pressure to recover methanol, the residual aqueous phase was extracted 3 times (3 × 15mL) with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the crude product was purified by column chromatography (elution solvent was ethyl acetate: petroleum ether ═ 1:5, volume ratio) to obtain 3.14g of reddish brown liquid which was 3-ethynylaniline, yield 88%.

Example 5

6.05g (40mmoL) of 3-nitroethylbenzene, 4.16g (27.6mmoL) of sodium bromate, 5.64g (54.8mmoL) of sodium bromide, 35mL of dichloroethane and 3mL of water are sequentially added into a 100mL flask, the flask is provided with a stirring and refluxing condenser and a thermometer, the flask is heated to reflux, 1/3 volumes of initiator solution (obtained by dissolving 0.15g of azobisisobutyronitrile in 5mL of dichloroethane) are rapidly added, after violent reflux of the system occurs, 4.04g of sulfuric acid (obtained by diluting 41.2mmoL concentrated sulfuric acid with 1mL of water) and the rest of initiator solution are slowly added, the flask is tracked by thin layer chromatography, the temperature is reduced to room temperature after the reaction is finished, 10mL of saturated sodium bisulfite solution is added for reaction for 5 minutes, liquid separation is carried out, the aqueous phase is extracted for 3 times by dichloroethane (3x10mL), the organic phases are combined, anhydrous sodium sulfate is dried, filtered and the filtrate is concentrated under reduced pressure to obtain light yellow solid, the filtrate is 1, 1-dibromo-1- (3-nitrophenyl) ethane crude product.

At room temperature, 50mL of absolute ethyl alcohol and 3.95g (70.6mmoL) of potassium hydroxide are added into a 100mL three-necked flask, the mixture is uniformly stirred, the crude product of the 1, 1-dibromo-1- (3-nitrophenyl) ethane obtained by bromination reaction is added in batches, the temperature is raised to 40-60 ℃ by stirring, and the reaction process is tracked by thin layer chromatography. After the reaction, filtration was carried out, the solid was recovered and reused, the filtrate was concentrated under reduced pressure, and the crude product was purified by column chromatography (the elution solvent was ethyl acetate: petroleum ether: 1:60 by volume) to obtain 4.47g of a reddish brown liquid which was 3-nitrophenylacetylene, with a yield of 76% in the two steps.

At room temperature, 30mL of water and 3.41g (90mmoL) of iron powder are added into a reaction bottle, 0.3mL of concentrated hydrochloric acid is dropwise added under stirring, a 3-nitrophenylacetylene methanol solution (4.47g, a solution obtained by dissolving 30.4mmoL of 3-nitrophenylacetylene in 30mL of methanol) is dropwise added, after the dropwise addition is finished, a heating reflux reaction is carried out, and the reaction progress is tracked by a thin layer chromatography. After the reaction was completed, the reaction mixture was cooled to room temperature, the residue was filtered off, the filtrate was concentrated under reduced pressure to recover methanol, the residual aqueous phase was extracted 3 times (3 × 15mL) with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the crude product was purified by column chromatography (elution solvent was ethyl acetate: petroleum ether ═ 1:5, volume ratio) to obtain 3.14g of reddish brown liquid which was 3-ethynylaniline, yield 93%.

Example 6

6.05g (40mmoL) of 3-nitroethylbenzene, 4.16g (27.6mmoL) of sodium bromate, 5.64g (54.8mmoL) of sodium bromide, 35mL of dichloroethane and 3mL of water are sequentially added into a 100mL flask, the flask is provided with a stirring and refluxing condenser and a thermometer, the flask is heated to reflux, 1/3 volumes of initiator solution (obtained by dissolving 0.3g of azobisisobutyronitrile in 5mL of dichloroethane) are rapidly added, after violent reflux of the system occurs, 4.04g of sulfuric acid (obtained by diluting 41.2mmoL concentrated sulfuric acid with 1mL of water) and the rest of initiator solution are slowly added, the flask is tracked by thin layer chromatography, the temperature is reduced to room temperature after the reaction is finished, 10mL of saturated sodium bisulfite solution is added for reaction for 5 minutes, liquid separation is carried out, the aqueous phase is extracted for 3 times by dichloroethane (3x10mL), the organic phases are combined, anhydrous sodium sulfate is dried, filtered and the filtrate is concentrated under reduced pressure to obtain light yellow solid, the filtrate is 1, 1-dibromo-1- (3-nitrophenyl) ethane crude product.

At room temperature, 50mL of absolute ethyl alcohol and 2.92g (73mmoL) of sodium hydroxide are added into a 100mL three-necked flask, the mixture is uniformly stirred, the crude product of the 1, 1-dibromo-1- (3-nitrophenyl) ethane obtained by bromination reaction is added in batches, the mixture is stirred and heated to 40-60 ℃, and the reaction process is tracked by thin-layer chromatography. After the reaction, filtration was carried out, the solid was recovered and reused, the filtrate was concentrated under reduced pressure, and the crude product was purified by column chromatography (the elution solvent was ethyl acetate: petroleum ether: 1:60 by volume) to obtain 4.94g of a reddish brown liquid which was 3-nitrophenylacetylene, with a yield of 84% in both steps.

At room temperature, 30mL of water and 3.76g (67.2mmoL) of iron powder are added into a reaction bottle, 0.25mL of concentrated hydrochloric acid is dropwise added under stirring, a 3-nitrophenylacetylene methanol solution (a solution obtained by dissolving 4.94g of 33.6mmoL of 3-nitrophenylacetylene in 30mL of methanol) is dropwise added, and after the dropwise addition is finished, the heating reflux reaction is carried out, and the reaction progress is tracked by a thin layer chromatography. After the reaction was completed, the reaction mixture was cooled to room temperature, the residue was filtered off, the filtrate was concentrated under reduced pressure to recover methanol, the residual aqueous phase was extracted 3 times (3 × 15mL) with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the crude product was purified by column chromatography (elution solvent was ethyl acetate: petroleum ether ═ 1:5, volume ratio) to obtain 3.66g of reddish brown liquid which was 3-ethynylaniline, yield 93%.

Example 7

6.05g (40mmoL) of 4-nitroethylbenzene, 4.16g (27.6mmoL) of sodium bromate, 5.64g (54.8mmoL) of sodium bromide, 35mL of dichloroethane and 3mL of water are sequentially added into a 100mL flask, the flask is equipped with a stirring, refluxing condenser and a thermometer, the flask is heated to reflux, 1/3 volumes of initiator solution (obtained by dissolving 0.15g of azobisisobutyronitrile in 5mL of dichloroethane) are rapidly added, after vigorous reflux of the system occurs, 4.04g of sulfuric acid (obtained by diluting 41.2mmoL of concentrated sulfuric acid with 1mL of water) and the rest of initiator solution are slowly added dropwise, the flask is followed by thin layer chromatography, the reaction is cooled to room temperature after the reaction is finished, 10mL of saturated sodium bisulfite solution is added for reaction for 5 minutes, liquid separation is carried out, the aqueous phase is extracted 3 times with dichloroethane (3x10mL), the organic phases are combined, anhydrous sodium sulfate is dried, the filtrate is filtered and concentrated under reduced pressure, the crude product is purified (the elution solvent is ethyl acetate: petroleum ether column chromatography: 1:30, volume ratio) to obtain a pale yellow solid, 12.36g of the solid, 1- (1, 1-dibromoethyl) -4-nitrobenzene, and the yield is 88%.¹H NMR(600MHz,CDCl₃)δ8.21(dd,J＝9.4,2.2Hz,2H),7.96–7.93(m,2H),3.00(s,3H)；¹³C NMR(151MHz,CDCl₃)δ152.1,147.6,127.2,123.4,58.6,40.7.。

At room temperature, 15mL of absolute ethyl alcohol and 0.84g (21mmoL) of sodium hydroxide are added into a 100mL three-neck flask, stirred uniformly, 3.09g (10mmoL) of 1- (1, 1-dibromoethyl) -4-nitrobenzene is added in batches, stirred and heated to 40-60 ℃, and the progress of the reaction is tracked by thin layer chromatography. Filtering after reaction, recovering solid, concentrating the filtrate under reduced pressure, and purifying the crude product by column chromatography (eluting solvent is B)Ethyl ester acid: petroleum ether-1: 60 by volume) gave 1.37g of a yellow solid as 4-nitrophenylacetylene in 93% yield.¹H NMR(600MHz,CDCl₃)δ8.21–8.17(m,2H),7.66–7.61(m,2H),3.36(s,1H)；¹³C NMR(151MHz,CDCl₃)δ147.5,132.9,128.8,123.5,82.3,81.5.

At room temperature, 10mL of water and 0.56g (10mmoL) of iron powder are added into a reaction bottle, 0.2mL of concentrated hydrochloric acid is dropwise added under stirring, a 4-nitrophenylacetylene methanol solution (0.74g, a solution obtained by dissolving 5mmoL of 4-nitrophenylacetylene in 10mL of methanol) is dropwise added, after the dropwise addition is finished, the heating reflux reaction is carried out, and the reaction process is tracked by a thin layer chromatography. After the reaction, the reaction mixture was cooled to room temperature, the filter residue was removed by filtration, the filtrate was concentrated under reduced pressure to recover methanol, the residual aqueous phase was extracted 3 times (3 × 15mL) with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the crude product was purified by column chromatography (the elution solvent was ethyl acetate: petroleum ether ═ 1:5, volume ratio) to give 0.54g of a reddish brown liquid which was 4-ethynylaniline, yield 92%.¹H NMR(600MHz,CDCl₃)δ7.31–7.28(m,2H),6.61–6.58(m,2H),3.82(s,2H),2.96(s,1H)；¹³C NMR(151MHz,CDCl₃)δ146.9,133.4,114.5,111.2,84.3,74.8.。

Example 8 (amplification experiment)

136.5g (0.9moL) of 3-nitroethylbenzene, 98g (0.65moL) of sodium bromate, 134g (1.3moL) of sodium bromide, 600mL of dichloroethane and 50mL of water are sequentially added into a 2L flask, the mixture is added into a reaction bottle provided with a stirring and refluxing condenser and a thermometer, the mixture is heated to reflux, about 10mL of initiator solution (obtained by dissolving 6g of azobisisobutyronitrile with 120mL of dichloroethane) is rapidly added, after violent reflux of the system occurs, sulfuric acid (obtained by diluting 0.98moL of concentrated sulfuric acid with 15mL of water) and the rest of initiator solution are slowly dropped, the mixture is tracked by thin layer chromatography, the temperature is reduced to room temperature after the reaction is finished, a proper amount of 10% saturated sodium bisulfite solution is added, the mixture is stirred for 5 minutes, the liquid is separated, the aqueous phase is extracted for 3 times (3x35mL) by dichloroethane, the organic phases are combined, and the dichloroethane is concentrated under. Recrystallizing the crude product by 270mL of absolute ethyl alcohol to obtain 220g of a product (the purity is 98 percent, and the yield is 79 percent); concentrating the recrystallization mother liquor under reduced pressure, recovering ethanol, adding 60mL of absolute ethanol into the residue, and recrystallizing to obtain 12g of a product (with the purity of 98%); the two crystallizations gave 232g of product (yield 83.3%).

At room temperature, 700mL of absolute ethyl alcohol and 64g (1.6moL) of sodium hydroxide are added into a 1L three-neck flask, the mixture is stirred uniformly, 232g (0.75moL) of 1, 1-dibromo-1- (3-nitrophenyl) ethane is added in batches, the temperature is raised to 40-60 ℃ by stirring, and the reaction progress is tracked by thin layer chromatography. After the reaction is finished, filtering and recovering sodium bromide solid, adding activated carbon into the filtrate for decolorization, filtering to remove the activated carbon, and concentrating the filtrate under reduced pressure to recover ethanol to obtain 102g of a crude product of the 3-nitrophenylacetylene (the yield is 92 percent and the purity is 95 percent).

At room temperature, 300mL of water and 78.4g (1.4moL) of iron powder are added into a reaction bottle, 4mL of concentrated hydrochloric acid is dropwise added under stirring, a 3-nitrophenylacetylene methanol solution (102g, a solution obtained by dissolving 0.69moL of 3-nitrophenylacetylene in 300mL of methanol) is dropwise added, heating reflux reaction is carried out after dropwise addition is finished, and the reaction progress is tracked by thin layer chromatography. After the reaction is finished, cooling to room temperature, filtering to remove filter residues, concentrating the filtrate under reduced pressure to recover methanol, extracting the residual water phase with ethyl acetate for 3 times (3x40mL), adjusting the pH of the residual water phase with 10% NaOH solution to be between 8 and 9, filtering again to remove the filter residues, extracting the water phase with ethyl acetate for 3 times (3x40mL), combining all organic phases, adding activated carbon for decolorization, filtering to remove the activated carbon, concentrating under reduced pressure to recover ethyl acetate, and obtaining 76.8g of 3-aminophenylacetylene (yield 95%, purity 96%) as a product.