Method for synthesizing propiolic acid ester compound based on N-benzyl methylene aziridine

Abstract

The invention relates to the technical field of chemical engineering, in particular to a method for synthesizing a propiolic acid ester compound based on N-benzyl methylene aziridine, which comprises the following steps: carrying out esterification reaction on a propiolic acid compound and an alcohol reagent in the presence of N-benzyl methylene aziridine to obtain the propiolic acid ester compound, and reacting in a reactor for 1-3 hours to obtain the propiolic acid ester compound. According to the method, N-benzyl methylene aziridine, a propiolic acid compound and an alcohol reagent are added, the mixture reacts for 24-48 hours at the room temperature, after the reaction is finished, the residual alcohol reagent participating in the reaction is dried by distillation, and the propiolic acid ester compound is obtained after purification, and the method has the advantages that the raw materials are cheap and easy to obtain, the operation is simple and convenient, the conditions are mild, and no catalyst needs to be added.

Description

Technical Field

[0001] The invention relates to the technical field of chemical industry, and in particular to a method for synthesizing propiolate compounds in the presence of N-benzylmethyleneaziridine, wherein in the presence of N-benzylmethyleneaziridine, propiolate compounds and alcohols undergo esterification reaction to obtain propiolate compounds. Background Art

[0002] Propylenic acid ester compounds are widely used in medicine, materials, pesticides and other fields. This type of structure ( Figure 1 ) is commonly used in the preparation of bacteria and fungi drugs for the prevention and treatment of agricultural and food pollution, as well as natural products and key drug intermediates.

[0003] Traditional synthetic methods for synthesizing propiolate esters usually use phenylacetylene as a raw material to directly add and replace these compounds ( Figure 2 ), but it is flammable, explosive when exposed to high heat and has a low yield. For example, Takeo Saegusa et al. reported the use of phenylacetylene to react with carbon dioxide and methyl iodide to produce phenylpropiolic acid methyl ester, wherein the low reactivity, high energy consumption, poor selectivity of carbon dioxide and the high toxicity, volatility, side reaction risk and environmental problems of methyl iodide limit its wide application (Journal of the Chemical Society, Chemical Communications, 1974, (10), 380-1)( Figure 2 Sarhan, AEWA et al. reported the reaction of phenylacetylene and methyl chloroformate to produce methyl phenylpropiolate, wherein methyl chloroformate has high toxicity, corrosiveness, instability and safety risks (Journal of Heterocyclic Chemistry, 2002, 39 (4), 691-694) ( Figure 2 , b). I. Chiarotto and I. Carelli reported the use of phenylacetylene and carbon monoxide and methanol to produce phenylpropiolic acid methyl ester, in which carbon monoxide has high toxicity, operation risks, harsh reaction conditions and catalyst dependence (Synthetic Communication, 2002, 32 (6), 881-886) ( Figure 2 , c).

[0004] In addition, using diazo compounds as raw materials and performing different addition reactions is also a common method for synthesizing propiolate compounds. For example, SP Ashburn and RM Coates reported the use of phenylpropiolic acid as a raw material and diazomethane in an ether solvent to generate phenylpropiolic acid methyl ester (Journal of Organic Chemistry, 1984, 49 (17), 3127-33.) Figure 3 ,a). Yasuhiro, Uozumi, Yukinari, & Kobayashi reported the use of Sonogashira coupling reaction, using Pd / Cu catalyzed cross-coupling reaction of organic halides and terminal alkynes, iodobenzene as raw material reacted with propiolic acid and diazomethane to generate phenylpropiolic acid methyl ester compound (Heterocycles, 2003, 59 (1), 71-74) ( Figure 3 , b). Shibuya, Masatoshi reported the use of 1-Me-ZADO (cat.), NaOCl (cat.) and NaClO 2 The combination of the two methods achieved an organic catalytic one-pot oxidative cleavage of the terminal 1,2-diol to a one-carbon unit shorter carboxylic acid under mild conditions, and then treated with diazomethane to obtain phenylpropiolic acid methyl ester (Organic Letters, 2012, 14 (19), 5006-5009) ( Figure 3 ,c). Cai, Rong used gold-catalyzed cross-coupling reaction with aryl diazonium salt as coupling reagent to obtain phenylpropiolic acid methyl ester from aryl diazonium and methyl propiolate (Angewandte Chemie, International Edition, 2015, 54 (30), 8772-8776) ( Figure 3 ,d). Most of the above methods require the use of diazo compounds, which are toxic, explosive, and carcinogenic, and the raw materials are difficult to synthesize. Summary of the invention

[0005] The purpose of the present invention is to solve the above problems and provide a method for synthesizing propiolate compounds in the presence of N-benzylmethyleneaziridine, which realizes the esterification reaction at room temperature. The method has cheap and readily available raw materials, is easy to operate, has mild conditions, does not require the addition of a catalyst, and has high safety and yield.

[0006] To solve the above problems, the technical solution adopted by the present invention is: a method for synthesizing propiolate compounds based on N-benzylmethyleneaziridine, in which alcohol and propiolate compounds are used as raw materials to synthesize propiolate compounds in the presence of N-benzylmethyleneaziridine, and the reaction formula is as follows: ; Where R 1C 1 -C 8 Alkyl, C 3 -C 8 One of cycloalkyl, phenyl, substituted phenyl, naphthyl, benzyl, substituted benzyl, the substituent on the phenyl or benzyl is C 1 -C 8 Alkyl, C 1 -C 8 Alkoxy, F, Cl, Br, I, NO 2 One, two or three of the following; R 2 is aryl or alkyl, wherein alkyl is C 1 -C 6 Chain alkyl or C 3 -C 8 Cyclic alkyl, aryl is substituted phenyl, naphthyl, thienyl, furanyl, pyridyl, the substituent on phenyl is C 1 -C 8 Alkyl, C 1 -C 8 Alkoxy, F, Cl, Br, I, NO 2 One, two or three of them.

[0007] Further, the following steps are included: In a reactor, N-benzylmethyleneaziridine, propiolic acid compounds and alcohol reagents are added, and the reaction is carried out at room temperature for 24-48 hours. After the reaction is completed, the alcohol reagent remaining after the reaction is evaporated to dryness, and the propiolic acid ester compound is obtained after purification.

[0008] Furthermore, the molar ratio of N-benzylmethyleneaziridine to the propiolic acid compound is 1:10-10:1.

[0009] Furthermore, the alcohol reagent is methanol, ethanol, n-propanol, isopropanol, n-butanol, sec-butanol, tert-butanol, isobutanol, n-pentanol, n-hexanol or benzyl alcohol.

[0010] Furthermore, the molar amount (mmol) of N-benzylmethyleneaziridine: the amount (mL) of the alcohol reagent = 1:1-1:30.

[0011] The present invention adopts the above technical scheme, and has the following advantages compared with the prior art: N-benzyl methylene aziridine is a three-membered cyclic compound with rich chemical properties and relatively stable existence, and N-benzyl methylene aziridine can undergo esterification reaction with alcohol solvents and propiolic acid compounds at room temperature to obtain propiolic acid ester compounds. The starting raw materials of the method are cheap and easy to obtain, the operation is simple, the conditions are mild, and no catalyst needs to be added. BRIEF DESCRIPTION OF THE DRAWINGS

[0012] Attached Figure 1 is the chemical formula of propiolate compound; Attached Figure 2 This is the chemical formula for the synthesis of propiolate compounds using phenylacetylene as a raw material; Attached Figure 3 It is the chemical formula of phenylpropiolate compounds currently synthesized using other methods. DETAILED DESCRIPTION

[0013] ; As shown in the above reaction formula, N-benzylmethyleneaziridine, propiolic acid compounds, and alcohol reagents are added to a reaction bottle and reacted at room temperature for 24-48 hours. After the reaction is completed, the alcohol reagent is removed by rotary evaporation, and the residue is chromatographed by silica gel column to obtain propiolic acid ester compounds.

[0014] Example 1 ; The reaction was carried out in a 10 ml reaction tube, 0.1 mmol of N-benzylmethyleneaziridine, 0.2 mmol of phenylpropiolic acid, and 3 ml of methanol were added, and the reaction was carried out at 25°C for 1 day. After the reaction was completed, the solvent was drained by a rotary evaporator, and the solid was subjected to silica gel column chromatography. The column was washed with an eluent of petroleum ether: ethyl acetate = 10:1 to obtain the product phenylpropiolic acid methyl ester, and the isolation yield was 87%. The nuclear magnetic resonance spectrum and mass spectrum data are shown below: 1 H NMR (300 MHz, CDCl 3 ) d 7.64–7.53 (m,2H), 7.52–7.30 (m, 3H), 3.84 (s, 3H). 13 C NMR (75 MHz, CDCl 3 ) d 154.6, 133.1,130.8, 128.7, 119.7, 86.6, 80.5, 53.0. ESI-MS: m / z=161 [M+H] + .

[0015] Example 2 ; The reaction was carried out in a 10 ml reaction tube, 0.3 mmol of N-benzylmethyleneaziridine, 0.2 mmol of p-methoxyphenylpropiolic acid, 5 ml of methanol were added, and the reaction was carried out at 25°C for 2 days. After the reaction, the solvent was drained by rotary evaporator, and the solid was subjected to silica gel column chromatography. The column was washed with an eluent of petroleum ether: ethyl acetate = 5:1 to obtain the product p-methoxyphenylpropiolic acid methyl ester, and the separation yield was 70%. The nuclear magnetic resonance spectrum and mass spectrum data are shown below: 1 H NMR (200 MHz, CDCl 3 ) d 7.53 (d, J = 9.0 Hz, 2H), 6.88 (d, J = 8.9 Hz, 2H), 3.83 (s, 3H), 3.82 (s, 3H). 13 CNMR (101 MHz, CDCl 3 ) d 161.7, 154.8, 135.0, 114.4, 111.4, 87.5, 79.9, 55.5,52.8. ESI-MS: m / z=191 [M+H] + .

[0016] Example 3 ; The reaction was carried out in a 10 ml reaction tube, 0.1 mmol of N-benzylmethyleneaziridine, 1 mmol of 2-trifluoromethylphenylpropiolic acid, 1 ml of methanol were added, and the reaction was carried out at 25°C for 2 days. After the reaction was completed, the solvent was drained by a rotary evaporator, and the solid was subjected to silica gel column chromatography. The column was washed with an eluent of petroleum ether: ethyl acetate = 8:1 to obtain the product 2-trifluoromethylphenylpropiolic acid methyl ester, and the separation yield was 85%. The nuclear magnetic resonance spectrum and mass spectrum data are shown below: 1 H NMR (400 MHz, CDCl 3 ) d 7.77 – 7.68 (m, 2H), 7.60 – 7.51 (m, 2H), 3.85 (s, 3H). 13 C NMR (101MHz, CDCl 3 ) d 154.1, 135.4, 133.0 (q, J (C–F) = 31.3 Hz), 131.8 (q, J (C–F) = 31.3 Hz),130.5, 126.3 (q,J (C–F) = 5.0 Hz), 123.1 (q, J (C–F) = 274 Hz), 84.9 (q, J (C–F) = 1.4Hz), 81.6, 53.1. ESI-MS: m / z= 229 [M+H] + .

[0017] Example 4 ; The reaction was carried out in a 10 ml reaction tube, and 0.05 mmol of N-benzylmethyleneaziridine, 0.3 mmol of p-fluorophenylpropiolic acid, and 1.5 ml of methanol were added, and the reaction was carried out at 25°C for 1 day. After the reaction was completed, the solvent was drained by a rotary evaporator, and the solid was subjected to silica gel column chromatography. The column was washed with an eluent of petroleum ether: ethyl acetate = 12:1 to obtain the product 4-fluorophenylpropiolic acid methyl ester, and the separation yield was 88%. The nuclear magnetic resonance spectrum and mass spectrum data are shown below: 1 H NMR (200 MHz, CDCl 3 ) d 7.66 –7.51 (m, 2H), 7.15 – 6.98 (m, 2H), 3.84 (s, 3H). 13 C NMR (50 MHz, CDCl 3 ) d 164.08(d, J (C–F) = 253.5 Hz), 154.51, 135.41 (d, J (C–F) = 8.9 Hz), 116.29 (d, J (C–F) = 22.3Hz), 115.78 (d, J (C–F) = 3.6 Hz), 85.59, 80.40 (d, J (C–F) = 1.6 Hz), 52.99. ESI-MS: m / z= 179 [M+H] + .

[0018] Example 5 ; The reaction was carried out in a 10 ml reaction tube, and 0.2 mmol of N-benzylmethyleneaziridine, 0.03 mmol of p-nitrophenylpropiolic acid, and 0.5 ml of methanol were added, and the reaction was carried out at 25°C for 2 days. After the reaction was completed, the solvent was drained by a rotary evaporator, and the solid was subjected to silica gel column chromatography. The column was washed with an eluent of petroleum ether: ethyl acetate = 3:1 to obtain the product p-nitrophenylpropiolic acid methyl ester, and the separation yield was 70%. The nuclear magnetic resonance spectrum and mass spectrum data are shown below: 1 H NMR (400 MHz, CDCl 3 ) d 8.25(d, J = 9.0 Hz, 2H), 7.75 (d, J = 8.9 Hz, 2H), 3.87 (s, 3H). 13 C NMR (101 MHz, CDCl 3 ) d 153.9, 148.7, 133.9, 126.4, 123.9, 84.0, 83.3, 53.3. ESIMS: m / z= 206[M+H] + .

[0019] Example 6 ; The reaction was carried out in a 10 ml reaction tube, and 0.1 mmol of N-benzylmethyleneaziridine, 0.7 mmol of phenylpropiolic acid, and 1.5 ml of isopropanol were added, and the reaction was carried out at 25°C for 2 days. After the reaction was completed, the solvent was drained by a rotary evaporator, and the solid was subjected to silica gel column chromatography. The column was washed with an eluent of petroleum ether: ethyl acetate = 15:1 to obtain the product phenylpropiolic acid isopropyl ester, and the separation yield was 80%. The nuclear magnetic resonance spectrum and mass spectrum data are shown below: 1 H NMR (200 MHz, CDCl 3 ) d 7.66 – 7.53(m, 1H), 7.49 – 7.30 (m, 2H), 5.16 (hept, J = 6.2 Hz, 1H), 1.34 (d, J = 6.3 Hz,3H). 13 C NMR (50 MHz, CDCl 3 ) d 153.8, 133.1, 130.6, 128.7, 119.9, 85.8, 81.2,70.2, 21.9. ESI-MS: m / z= 189 [M+H] + .

[0020] Example 7 ; The reaction was carried out in a 10 ml reaction tube, and 0.5 mmol of N-benzylmethyleneaziridine, 0.2 mmol of phenylpropiolic acid, and 0.5 ml of tert-butyl alcohol were added, and the reaction was carried out at 25°C for 1 day. After the reaction was completed, the solvent was drained by a rotary evaporator, and the solid was subjected to silica gel column chromatography. The column was washed with an eluent of petroleum ether: ethyl acetate = 12:1 to obtain the product tert-butyl phenylpropiolic acid, and the isolation yield was 75%. The nuclear magnetic resonance spectrum and mass spectrum data are shown below: 1 H NMR (200 MHz, CDCl 3 ) d 7.65 – 7.49 (m, 2H), 7.49 – 7.28 (m, 3H), 1.54 (s, 9H). 13 C NMR (50 MHz, CDCl 3 ) d 153.3,133.0, 130.4, 128.6, 120.1, 83.9, 83.7, 82.2, 28.2. ESI-MS: m / z= 203 [M+H] + .

[0021] Example 8 ; The reaction was carried out in a 10 ml reaction tube, and 1 mmol of N-benzylmethyleneaziridine, 0.1 mmol of phenylpropiolic acid, and 1 ml of phenylethanol were added, and the reaction was carried out at 25°C for 2 days. After the reaction was completed, the solvent was drained by a rotary evaporator, and the solid was subjected to silica gel column chromatography. The column was washed with an eluent of petroleum ether: ethyl acetate = 7:1 to obtain the product phenylpropiolic acid benzyl ester, and the isolation yield was 73%. The nuclear magnetic resonance spectrum and mass spectrum data are shown below: 1 H NMR (200 MHz, CDCl 3 ) d 7.64 – 7.52 (m,2H), 7.52 – 7.28 (m, 8H), 5.27 (s, 2H). 13 C NMR (101 MHz, CDCl 3 ) d 154.0, 135.1,133.2, 130.8, 128.81, 128.76, 128.7, 119.7, 86.9, 80.6, 67.9. ESI-MS: m / z=237 [M+H] + .

[0022] Example 9 ; The reaction was carried out in a 10 ml reaction tube, and 0.05 mmol of N-benzylmethyleneaziridine, 0.2 mmol of phenylpropiolic acid, and 1 ml of cyclopentanol were added, and the reaction was carried out at 25°C for 2 days. After the reaction was completed, the solvent was drained by a rotary evaporator, and the solid was subjected to silica gel column chromatography. The column was washed with an eluent of petroleum ether: ethyl acetate = 5:1 to obtain the product phenylpropiolic acid cyclopentyl ester, and the separation yield was 90%. The nuclear magnetic resonance spectrum and mass spectrum data are shown below: 1 H NMR (400 MHz, CDCl 3 ) d 7.61 – 7.55(m, 2H), 7.47 – 7.41 (m, 1H), 7.40 – 7.33 (m, 2H), 5.35 – 5.27 (m, 1H), 2.00 – 1.86 (m, 2H), 1.86 – 1.72 (m, 4H), 1.69 – 1.59 (m, 2H). 13 C NMR (101 MHz, CDCl 3 ) d 154.1, 133.1, 130.6, 128.7, 119.9, 85.8, 81.3, 79.4, 32.8, 23.9. ESI-MS: m / z= 215 [M+H] + .

[0023] Example 10 ; The reaction was carried out in a 10 ml reaction tube, and 0.6 mmol of N-benzylmethyleneaziridine, 0.1 mmol of phenylpropiolic acid, and 3 ml of 1-phenylethanol were added, and the reaction was carried out at 25°C for 1 day. After the reaction was completed, the solvent was drained by a rotary evaporator, and the solid was subjected to silica gel column chromatography. The column was washed with an eluent of petroleum ether: ethyl acetate = 6:1 to obtain the product phenylpropiolic acid phenethyl ester, and the isolation yield was 87%. The nuclear magnetic resonance spectrum and mass spectrum data are shown below: 1 H NMR (400 MHz, CDCl 3 ) d 7.63 – 7.56(m, 2H), 7.49 – 7.29 (m, 8H), 6.04 (q, J = 6.6 Hz, 1H), 1.65 (d, J = 6.6 Hz, 3H). 13C NMR (101 MHz, CDCl 3 ) d 153.4, 140.7, 133.0, 130.7, 128.7, 128.6, 128.3,126.3, 119.7, 86.3, 81.0, 74.4, 22.1. ESI-MS: m / z= 251 [M+H] + .

[0024] Embodiment 11 ; The reaction was carried out in a 10 ml reaction tube, and 0.5 mmol of N-benzylmethyleneaziridine, 1.5 mmol of 4,4-dimethylpentan-2-nonanoic acid, and 7.5 ml of ethanol were added, and the reaction was carried out at 25°C for 1 day. After the reaction was completed, the solvent was drained by a rotary evaporator, and the solid was subjected to silica gel column chromatography. The column was washed with an eluent of petroleum ether: ethyl acetate = 12:1 to obtain the product 4,4-dimethyl-2-pentynoic acid ethyl ester, and the separation yield was 80%. The nuclear magnetic resonance spectrum and mass spectrum data are shown below: 1 H NMR (400 MHz, CDCl 3 ) d 4.20 (q, J = 7.1 Hz, 2H), 1.29 (t, J = 7.1 Hz, 3H), 1.27 (s, 9H); 13 C NMR (101 MHz, CDCl 3 ) d 154.3, 96.5, 72.0, 61.9, 30.1, 27.6, 14.2. HRMS (APCI + ):calcd for C 9 H 14 O 2 [M+H] + , 155.1067; found, 155.1059.

[0025] Example 12 ; The reaction was carried out in a 10 ml reaction tube, and 0.5 mmol of N-benzylmethyleneaziridine, 0.5 mmol of 3-cyclopentylprop-2-ynoic acid, and 1 ml of ethanol were added, and the reaction was carried out at 25°C for 2 days. After the reaction was completed, the solvent was drained by a rotary evaporator, and the solid was subjected to silica gel column chromatography. The column was washed with an eluent of petroleum ether: ethyl acetate = 10:1 to obtain the product 3-cyclopentylpropionic acid ethyl ester, and the isolation yield was 78%. The nuclear magnetic resonance spectrum and mass spectrum data are shown below: 1 H NMR (400 MHz, CDCl 3 ) d 4.18(q, J = 7.1 Hz, 2H), 2.74–2.67 (m, 1H), 1.94 – 1.89 (m, 2H), 1.75 – 1.61 (m,4H), 1.60 – 1.49 (m, 2H), 1.27 (t, J = 7.1 Hz, 3H). 13 C NMR (101 MHz, CDCl 3 ) d 154.1, 93.4, 72.8, 61.8, 33.1, 29.8, 25.3, 14.2. HRMS (APCI + ):calcd for C 10 H 15 O 2 [M+H] + , 167.1067; found, 167.1065.

[0026] Embodiment 13 ; The reaction was carried out in a 10 ml reaction tube, and 0.5 mmol of N-benzylmethyleneaziridine, 2.5 mmol of 3-(naphthalene-1-yl)prop-2-ynoic acid, and 5 ml of methanol were added, and the reaction was carried out at 25°C for 2 days. After the reaction, the solvent was drained by a rotary evaporator, and the solid was subjected to silica gel column chromatography. The column was washed with an eluent of petroleum ether: ethyl acetate = 5:1 to obtain the product 2-propynoic acid 3-(1-naphthyl)-methyl ester, and the separation yield was 79%. The nuclear magnetic resonance spectrum and mass spectrum data are shown below: 1 H NMR (400 MHz, CDCl 3 ) d 8.14 (d, J = 8.2 Hz, 1H), 7.75 – 7.60 (m, 3H), 7.45 – 7.38 (m, 1H), 7.33(dd,J = 7.9, 7.1 Hz, 1H), 7.27 – 7.16 (m, 1H), 3.71 (s, 3H). 13 C NMR (101 MHz, CDCl 3 ) d 154.6, 133.6, 133.1, 133.0, 131.4, 128.5, 127.7, 126.9, 125.7, 125.1,117.0, 85.1, 84.9, 52.8. HR-MS calc: m / z=210.0681 found: m / z=210.0682.

[0027] The above shows and describes the basic principles, main features and advantages of the present invention. It should be understood by those skilled in the art that the present invention is not limited to the above embodiments. The above embodiments and descriptions are only for explaining the principles of the present invention. Without departing from the spirit and scope of the present invention, the present invention may have various changes and improvements, which fall within the scope of the present invention. The scope of protection of the present invention is defined by the attached claims and their equivalents.

Claims

1. A method for synthesizing propiolate compounds based on N-benzylmethyleneaziridine, characterized in that: In the presence of N-benzylmethyleneaziridine, alcohol and propiolic acid compounds are used as raw materials to synthesize propiolic acid ester compounds. The reaction formula is as follows: ; Wherein R1 is one of C1-C8 alkyl, C3-C8 cycloalkyl, phenyl, substituted phenyl, naphthyl, benzyl, substituted benzyl, and the substituent on the phenyl or benzyl group is one, two or three of C1-C8 alkyl, C1-C8 alkoxy, F, Cl, Br, I, and NO2; R2 is an aryl group or an alkyl group, wherein the alkyl group is a C1-C6 chain alkyl group or a C3-C8 cyclic alkyl group, the aryl group is a substituted phenyl group, a naphthyl group, a thienyl group, a furyl group, or a pyridyl group, and the substituent on the phenyl group is one, two, or three of a C1-C8 alkyl group, a C1-C8 alkoxy group, F, Cl, Br, I, or NO2.

2. The method according to claim 1, characterized in that The following steps are involved: In a reactor, N-benzylmethyleneaziridine, propiolic acid compounds and alcohol reagents are added, and the reaction is carried out at room temperature for 24-48 hours. After the reaction is completed, the alcohol reagent remaining after the reaction is evaporated to dryness, and the propiolic acid ester compound is obtained after purification.

3. The method according to claim 2, characterized in that: The molar ratio of N-benzylmethyleneaziridine to the propiolic acid compound is 1:10-10:

1.

4. The method according to claim 2, characterized in that: The alcohol reagent is methanol, ethanol, n-propanol, isopropanol, n-butanol, sec-butanol, tert-butanol, isobutanol, n-pentanol, n-hexanol or benzyl alcohol.

5. The method according to claim 2, characterized in that: The molar amount of N-benzylmethyleneaziridine (mmol): the amount of alcohol reagent used (mL) = 1:1-1:30.

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