A method for synthesizing propargyl esters based on N-benzylidene aziridine

Abstract

The present invention relates to the field of chemical engineering technology, and particularly to a method for synthesizing propargyl esters based on N-benzylideneaziridine. The propargyl esters are obtained by an esterification reaction of propargylic acid compounds and alcohol reagents in the presence of N-benzylideneaziridine. In a reactor, N-benzylideneaziridine, propargylic 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 remaining alcohol reagents participating in the reaction are evaporated to dryness, and the propargyl esters are obtained after purification. This method has cheap and easily available raw materials, simple operation, mild conditions, and does not require the addition of a catalyst.

Description

Technical Field

[0001] The present invention relates to the field of chemical engineering technology. Specifically, it relates to a method for synthesizing propargyl esters in the presence of N-benzylideneaziridine. In the presence of N-benzylideneaziridine, an esterification reaction occurs between a propargylic acid compound and an alcohol to obtain a propargyl ester compound. Background Art

[0002] Propargyl ester compounds are widely used in the fields of medicine, materials, pesticides, etc. Such structures ( Figure 1 ) are commonly used in the preparation of drugs for preventing and treating bacteria and fungi related to agricultural and food pollution, as well as key intermediates of natural products and drugs.

[0003] Traditional methods for synthesizing propargyl ester compounds usually use phenylacetylene as a raw material for direct addition and substitution to prepare such compounds ( Figure 2 ). However, it is flammable, prone to explosion when exposed to high heat, and has a low yield. For example, Takeo Saegusa et al. reported the reaction of phenylacetylene with carbon dioxide and iodomethane to form methyl phenylpropiolate. The low reactivity, high energy consumption requirements, poor selectivity of carbon dioxide, as well as the high toxicity, volatility, side reaction risk, and environmental problems of iodomethane limit its wide application (Journal of the Chemical Society, Chemical Communications, 1974, (10), 380 - 1) ( Figure 2 , a). Sarhan, A.E.W.A. et al. reported the reaction of phenylacetylene and methyl chloroformate to form methyl phenylpropiolate. 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 reaction of phenylacetylene with carbon monoxide and methanol to form methyl phenylpropiolate. Carbon monoxide has high toxicity, operational 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 conducting different addition reactions are also common synthesis methods for propargylate 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 methyl phenylpropiolate compounds (Journal of Organic Chemistry, 1984, 49(17), 3127 - 33.)( Figure 3 , a). Yasuhiro, Uozumi, Yukinari, & Kobayashi reported the use of the Sonogashira coupling reaction, a cross - coupling reaction of organic halides and terminal alkynes catalyzed by Pd / Cu. Using iodobenzene as a raw material, reacting with propargylic acid and diazomethane to generate methyl phenylpropiolate compounds (Heterocycles, 2003, 59(1), 71 - 74)( Figure 3 , b). Shibuya, Masatoshi reported that a combination of 1 - Me - ZADO (cat.), NaOCl (cat.) and NaClO2 achieved the organic - catalytic one - pot oxidative cleavage of terminal 1,2 - diols to carboxylic acids with shorter one - carbon units under mild conditions, and then obtained methyl phenylpropiolate after treatment with diazomethane (Organic Letters, 2012, 14(19), 5006 - 5009)( Figure 3 , c). Cai, Rong used a gold - catalyzed cross - coupling reaction with aryl diazonium salts as coupling reagents to obtain methyl phenylpropiolate from aryl diazo and methyl propargylate (Angewandte Chemie, International Edition, 2015, 54(30), 8772 - 8776)( Figure 3 , d). Most of the above - mentioned methods require the use of diazo compounds, which are toxic, explosive, and carcinogenic, and the synthesis of raw materials is difficult. Summary of the Invention

[0005] The object of the present invention is to solve the above problems by providing a method for synthesizing propargylate compounds in the presence of N - benzylideneaziridine, realizing an esterification reaction that can occur at room temperature. This method has cheap and easily available raw materials, simple operation, 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 propargylate compounds based on N - benzylideneaziridine. In the presence of N - benzylideneaziridine, alcohols and propargylic acid compounds are used as raw materials to synthesize propargylate compounds, and the reaction formula is as follows:

[0007] ;

[0008] Among them, R1 is one of C1-C8 alkyl, C3-C8 cycloalkyl, phenyl, substituted phenyl, naphthyl, benzyl, and substituted benzyl, and the substituents on the phenyl or benzyl are one, two or three of C1-C8 alkyl, C1-C8 alkoxy, F, Cl, Br, I, and NO2;

[0009] R2 is an alkyl group, where the alkyl group is a C1-C6 linear alkyl group or a C3-C8 cyclic alkyl group.

[0010] Furthermore, it includes the following steps:

[0011] In a reactor, add N-benzylideneaziridine, propargylic acid compounds, and alcohol reagents, and react at room temperature for 24-48 hours. After the reaction is completed, evaporate the remaining alcohol reagents after the reaction, and obtain propargylic acid ester compounds after purification.

[0012] Furthermore, the molar ratio of N-benzylideneaziridine to propargylic acid compounds is 1:10 - 10:1.

[0013] Furthermore, the alcohol reagents are methanol, ethanol, n-propanol, isopropanol, n-butanol, sec-butanol, tert-butanol, isobutanol, n-pentanol or n-hexanol.

[0014] Furthermore, the molar amount mmol of N-benzylideneaziridine: the dosage mL of the alcohol reagent = 1:1 - 1:30.

[0015] The present invention adopts the above technical solutions. Compared with the prior art, it has the following advantages: N-benzylideneaziridine is a ternary cyclic compound with rich chemical properties and relatively stable existence. At room temperature, N-benzylideneaziridine can react with alcohol solvents and propargylic acid compounds to obtain propargylic acid ester compounds. This method has cheap and easily available starting materials, simple operation, mild conditions, and does not require the addition of a catalyst. BRIEF DESCRIPTION OF THE DRAWINGS

[0016] Attached Figure 1 is the chemical formula of propargylic acid ester compounds;

[0017] Attached Figure 2 is the chemical formula of currently using phenylacetylene as the raw material to synthesize propargylic acid ester compounds;

[0018] Attached Figure 3 is the chemical formula of currently using other methods to synthesize phenylpropiolic acid ester compounds. DETAILED DESCRIPTION OF THE INVENTION

[0019] ;

[0020] As shown in the above reaction formula, N-benzylideneaziridine, propargylic acid compounds, and alcohol reagents are added to the reaction flask, and the reaction is carried out at room temperature for 24 - 48 hours. After the reaction is completed, the alcohol reagents are removed by rotary evaporation, and the residue is subjected to silica gel column chromatography to obtain propargylic acid ester compounds.

[0021] Example 1

[0022] ;

[0023] The reaction was carried out in a 10 ml reaction tube. 0.1 mmol of N-benzylideneaziridine and 0.2 mmol of phenylpropiolic acid were added, and 3 ml of methanol was added. The reaction was carried out at 25 °C for 1 day. After the reaction was completed, the solvent was dried by rotary evaporation, 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 methyl phenylpropiolate, and the separation yield was 87%. The nuclear magnetic resonance spectroscopy and mass spectrometry data are as follows: 1 H NMR (300 MHz, CDCl3) δ 7.64–7.53 (m,2H), 7.52–7.30 (m, 3H), 3.84 (s, 3H). 13 C NMR (75 MHz, CDCl3) δ 154.6, 133.1,130.8, 128.7, 119.7, 86.6, 80.5, 53.0. ESI-MS: m / z=161 [M+H] + 。

[0024] Example 2

[0025] ;

[0026] The reaction was carried out in a 10 ml reaction tube. 0.3 mmol of N-benzylideneaziridine and 0.2 mmol of p-methoxyphenylpropiolic acid were added, and 5 ml of methanol was added. The reaction was carried out at 25 °C for 2 days. After the reaction was completed, the solvent was dried by rotary evaporation, 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 methyl p-methoxyphenylpropiolate, and the separation yield was 70%. The nuclear magnetic resonance spectroscopy and mass spectrometry data are as follows: 1 H NMR (200 MHz, CDCl3) δ 7.53 (d, J = 9.0 Hz, 2H), 6.88 (d, J = 8.9 Hz, 2H), 3.83 (s, 3H), 3.82 (s,3H). 1313C NMR (101 MHz, CDCl3) δ 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] + 。

[0027] Example 3

[0028] ;

[0029] The reaction was carried out in a 10 ml reaction tube. 0.1 mmol of N-benzylideneaziridine and 1 mmol of 2-(trifluoromethyl)phenylpropiolic acid were added, and 1 ml of methanol was added. The reaction was carried out at 25 °C for 2 days. After the reaction was completed, the solvent was dried by rotary evaporation. The solid was subjected to silica gel column chromatography, and the column was washed with an eluent of petroleum ether:ethyl acetate = 8:1 to obtain methyl 2-(trifluoromethyl)phenylpropiolate, and the separation yield was 85%. The nuclear magnetic resonance spectroscopy and mass spectrometry data are as follows: 1 1H NMR (400 MHz, CDCl3) δ 7.77 – 7.68 (m, 2H), 7.60 – 7.51 (m, 2H), 3.85 (s, 3H). 13 13C NMR (101 MHz, CDCl3) δ 154.1, 135.4, 133.0 (q, J (C–F) J = 31.3 Hz), 131.8 (q, J (C–F) J = 31.3 Hz), 130.5, 126.3 (q, J (C–F) J = 5.0 Hz), 123.1 (q, J (C–F) J = 274 Hz), 84.9 (q, J (C –F) J = 1.4 Hz), 81.6, 53.1. ESI-MS: m / z = 229 [M+H] + 。

[0030] Example 4

[0031] ;

[0032] The reaction was carried out in a 10 ml reaction tube. 0.05 mmol of N-benzylideneaziridine, 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 dried by rotary evaporation, and the solid was subjected to silica gel column chromatography. The column was rinsed with an eluent of petroleum ether:ethyl acetate = 12:1 to obtain the product methyl p-fluorophenylpropionate, and the separation yield was 88%. The nuclear magnetic resonance spectroscopy and mass spectrometry data are as follows: 1 H NMR (200 MHz, CDCl3) δ 7.66 –7.51 (m, 2H), 7.15 – 6.98 (m, 2H), 3.84 (s, 3H). 13 C NMR (50 MHz, CDCl3) δ 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) = 22.3 Hz), 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] + 。

[0033] Example 5

[0034] ;

[0035] The reaction was carried out in a 10 ml reaction tube. 0.2 mmol of N-benzylideneaziridine, 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 dried by rotary evaporation, and the solid was subjected to silica gel column chromatography. The column was rinsed with an eluent of petroleum ether:ethyl acetate = 3:1 to obtain the product methyl p-nitrophenylpropionate, and the separation yield was 70%. The nuclear magnetic resonance spectroscopy and mass spectrometry data are as follows: 1 H NMR (400 MHz, CDCl3) δ 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, CDCl3) δ 153.9, 148.7, 133.9, 126.4, 123.9, 84.0, 83.3, 53.3. ESIMS: m / z = 206 [M+H] + 。

[0036] Example 6

[0037] ;

[0038] The reaction was carried out in a 10 ml reaction tube. 0.1 mmol of N-benzylidenaziridine, 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 dried by rotary evaporation, 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 isopropyl phenylpropiolate, and the separation yield was 80%. The nuclear magnetic resonance spectroscopy and mass spectrometry data are as follows: 1 H NMR (200 MHz, CDCl3) δ 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, CDCl3) δ 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] + 。

[0039] Example 7

[0040] ;

[0041] The reaction was carried out in a 10 ml reaction tube. 0.5 mmol of N-benzylidenaziridine, 0.2 mmol of phenylpropiolic acid, and 0.5 ml of tert-butanol were added, and the reaction was carried out at 25 °C for 1 day. After the reaction was completed, the solvent was dried by rotary evaporation, 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 phenylpropiolate, and the separation yield was 75%. The nuclear magnetic resonance spectroscopy and mass spectrometry data are as follows: 1 H NMR (200 MHz, CDCl3) δ7.65 – 7.49 (m, 2H), 7.49 – 7.28 (m, 3H), 1.54 (s, 9H). 13 13C NMR (50 MHz, CDCl3) δ 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] + 。

[0042] Example 8

[0043] ;

[0044] The reaction was carried out in a 10 ml reaction tube. 1 mmol of N-benzylideneaziridine, 0.1 mmol of phenylpropiolic acid, and 1 ml of phenethyl alcohol were added, and the reaction was carried out at 25 °C for 2 days. After the reaction was completed, the solvent was evaporated to dryness with a rotary evaporator, and the solid was subjected to silica gel column chromatography. The column was eluted with a eluent of petroleum ether:ethyl acetate = 7:1 to obtain the product benzyl phenylpropiolate, and the separation yield was 73%. The nuclear magnetic resonance spectroscopy and mass spectrometry data are as follows: 1 1H NMR (200 MHz, CDCl3) δ 7.64 – 7.52(m, 2H), 7.52 – 7.28 (m, 8H), 5.27 (s, 2H). 13 13C NMR (101 MHz, CDCl3) δ 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] + 。

[0045] Example 9

[0046] ;

[0047] The reaction was carried out in a 10 ml reaction tube. 0.05 mmol of N-benzylideneaziridine, 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 evaporated to dryness with a rotary evaporator, and the solid was subjected to silica gel column chromatography. The column was eluted with a eluent of petroleum ether:ethyl acetate = 5:1 to obtain the product cyclopentyl phenylpropiolate, and the separation yield was 90%. The nuclear magnetic resonance spectroscopy and mass spectrometry data are as follows: 1 1H NMR (400 MHz, CDCl3)δ 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, CDCl3) δ 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] + 。

[0048] Example 10

[0049] ;

[0050] The reaction was carried out in a 10 ml reaction tube. 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 dried by rotary evaporation, 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 phenethyl phenylpropiolate, and the separation yield was 87%. The nuclear magnetic resonance spectroscopy and mass spectrometry data are as follows: 1 H NMR (400 MHz, CDCl3) δ 7.63 –7.56 (m, 2H), 7.49 – 7.29 (m, 8H), 6.04 (q, J J = 6.6 Hz, 1H), 1.65 (d, J J = 6.6Hz, 3H). 13 C NMR (101 MHz, CDCl3) δ 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] + 。

[0051] Example 11

[0052] ;

[0053] The reaction was carried out in a 10 ml reaction tube. 0.5 mmol of N-benzylideneaziridine, 1.5 mmol of 4,4-dimethylpent-2-enoic 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 dried by rotary evaporation. The solid was subjected to silica gel column chromatography, and the column was washed with an eluent of petroleum ether:ethyl acetate = 12:1 to obtain ethyl 4,4-dimethyl-2-pentynoate, and the separation yield was 80%. The nuclear magnetic resonance spectroscopy and mass spectrometry data are as follows: 1 H NMR (400 MHz,CDCl3) δ 4.20 (q, J = 7.1 Hz, 2H), 1.29 (t, J = 7.1 Hz, 3H), 1.27 (s, 9H); 13 CNMR (101 MHz, CDCl3) δ 154.3, 96.5, 72.0, 61.9, 30.1, 27.6, 14.2. HRMS (APCI + ): calcd for C9H 14 O2 [M+H] + , 155.1067; found, 155.1059。

[0054] Example 12

[0055] ;

[0056] The reaction was carried out in a 10 ml reaction tube. 0.5 mmol of N-benzylideneaziridine, 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 dried by rotary evaporation. The solid was subjected to silica gel column chromatography, and the column was washed with an eluent of petroleum ether:ethyl acetate = 10:1 to obtain ethyl 3-cyclopentylpropionate, and the separation yield was 78%. The nuclear magnetic resonance spectroscopy and mass spectrometry data are as follows: 1 H NMR (400 MHz, CDCl3) δ 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,CDCl3)δ 154.1, 93.4, 72.8, 61.8, 33.1, 29.8, 25.3, 14.2. HRMS (APCI + ): calcd for C 10 H 15 O2 [M+H] + , 167.1067; found, 167.1065。

[0057] Example 13

[0058] ;

[0059] The reaction was carried out in a 10 ml reaction tube. 0.5 mmol of N-benzylideneaziridine, 2.5 mmol of 3-(naphthalen-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 was completed, the solvent was dried by rotary evaporation, and the solid was subjected to silica gel column chromatography. The column was washed with a eluent of petroleum ether:ethyl acetate = 5:1 to obtain the product methyl 3-(1-naphthyl)prop-2-ynoate, and the separation yield was 79%. The nuclear magnetic resonance spectrum and mass spectrometry data are as follows: 1 H NMR (400 MHz, CDCl3) δ 8.14 (d, J J = 8.2 Hz, 1H), 7.75 – 7.60 (m, 3H), 7.45 – 7.38 (m, 1H), 7.33 (dd, J J = 7.9, 7.1 Hz, 1H), 7.27 – 7.16 (m, 1H), 3.71 (s, 3H). 13 C NMR(101 MHz, CDCl3) δ 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。

[0060] The basic principles, main features and advantages of the present invention have been shown and described above. Those skilled in the art should understand that the present invention is not limited by the above embodiments. What is described in the above embodiments and the specification only illustrates the principles of the present invention. Without departing from the spirit and scope of the present invention, the present invention will have various changes and improvements, and these changes and improvements all fall within the scope of the present invention claimed. The scope of protection claimed by the present invention is defined by the appended claims and their equivalents.

Claims

1. A method for synthesizing propargyl esters based on N-benzylideneaziridine, characterized in that, Using an alcohol and a propiolic acid compound as raw materials, a propiolate compound is synthesized in the presence of N-benzylideneaziridine. The reaction formula is as follows: ； Wherein R1 is one of C1-C8 alkyl, C3-C8 cycloalkyl, phenyl, substituted phenyl, naphthyl, benzyl, and substituted benzyl, and the substituents on the phenyl or benzyl are one, two, or three of C1-C8 alkyl, C1-C8 alkoxy, F, Cl, Br, I, and NO2; R2 is an alkyl group, and the alkyl group is a C1-C6 linear alkyl group or a C3-C8 cyclic alkyl group.

2. The method according to claim 1, characterized in that, It includes the following steps: In a reactor, add N-benzylideneaziridine, a propiolic acid compound, and an alcohol reagent, and react at room temperature for 24-48 hours. After the reaction is completed, evaporate the remaining alcohol reagent after the reaction, and obtain the propiolate compound after purification.

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

1.

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

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

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