CN113200980A - Method for synthesizing indolizine compound under catalysis of silver - Google Patents
Method for synthesizing indolizine compound under catalysis of silver Download PDFInfo
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Abstract
The invention discloses a method for synthesizing indolizine compounds under the catalysis of silver, which takes N-phenacyl pyridinium bromide shown in a formula (1) and isocyanide compounds shown in a formula (2) as raw materials in an organic solvent system, wherein the feeding molar ratio of the N-phenacyl pyridinium bromide to the isocyanide compounds is 1: (1.2-2.0), taking a metal silver salt as a catalyst, stirring in the air for reaction under an alkaline condition, tracking and detecting by TLC until the reaction is complete, and carrying out post-treatment on the reaction liquid to obtain the indolizine compound shown in the formula (3). The method has the advantages of simple operation, easily obtained raw materials and reagents, mild reaction conditions, green and environment-friendly reaction system, easy separation and purification of products, high yield of 91 percent, suitability for preparing indolizine compounds with high efficiency and high yield, and particular suitability for synthesizing various 1, 2-substituted indolizine compounds. The invention is suitable for large-scale industrial production, and has wide application prospect and important significance in organic synthesis.
Description
Technical Field
The invention belongs to the technical field of fine chemical organic synthesis, and particularly relates to a method for synthesizing indolizine compounds under the catalysis of silver.
Background
Indolizine (Indolizine), also known as Indolizine, is an isomer with indole and isoindole, is a common nitrogen fused heterocyclic compound with 10 pi electron system, and is an important structural unit of many natural products and drug molecules. Because of the unique biological and pharmacological activities of antivirus, antibiosis, anti-inflammation, antihypertensive, antitumor and the like, the indolizine derivative has wide application in the fields of medicine, pesticide, biology and the like. For example, Swainsonine (Swainsonine) inhibits α -mannosidase II in the Golgi complex and thus inhibits N-linked oligosaccharide synthesis in malignant cells. Lamellarin (Lamellarin) is a series of pyrrole alkaloid compounds which are separated from marine mollusks and have stronger physiological activity and complex structures, has good antitumor and antiviral effects and has good prospects in preventing human cancers. In addition, the indolizine derivative can also be used as a fluorescent probe and a semiconductor material in the fields of analytical chemistry and material science.
For the synthetic studies of indolizine and derivatives thereof, various methods have been developed, and the most common synthetic methods include Scholtz condensation, Tschirschibabin reaction, 1, 3-dipolar cycloaddition reaction, and the like. However, these synthetic methods have drawbacks such as the need for high temperature and high pressure, the need for large amounts of base and equivalent or excess amounts of oxidizing agent, inconvenient operation, low yield, etc. Therefore, the development of a novel and practical method for synthesizing indolizine compounds is of great significance.
Disclosure of Invention
The invention aims to provide a method for synthesizing indolizine compounds under the catalysis of silver, which can improve the yield, and has the advantages of easily available raw materials, simple operation and mild reaction conditions.
In order to achieve the purpose, the technical scheme adopted by the invention is as follows: a method for synthesizing indolizine compounds through silver catalysis is characterized in that in an organic solvent system, N-phenacyl pyridinium bromide shown in a formula (1) and isocyanides shown in a formula (2) are used as raw materials, metal silver salt is used as a catalyst, stirring is carried out in the air for reaction, TLC tracking detection is carried out until the reaction is complete, and the indolizine compounds shown in a formula (3) are obtained after post-treatment of reaction liquid;
the organic solvent is one of 1, 2-dichloroethane, 1, 4-dioxane, N-dimethylformamide, acetonitrile, dimethyl sulfoxide, toluene and tetrahydrofuran;
the metal silver salt is one of silver carbonate, silver nitrate, silver oxide, silver fluoride, silver nitrite, silver acetate, silver trifluoromethanesulfonate and silver tetrafluoroborate;
the alkali is one of potassium carbonate, cesium carbonate, triethylamine and DBU;
the feeding molar ratio of the N-phenacyl pyridinium bromide to the isocyanic compounds is 1: (1.2-2.0);
wherein R is1Is hydrogen, phenyl, alkyl, alkoxy, nitro or halogen atom, R2Is methyl or ethyl.
Preferably, the metal silver salt is silver carbonate.
Preferably, the amount of the metal silver salt is 1.0 to 2.0 times the amount of the substance of N-phenacyl pyridinium bromide represented by the formula (1).
Preferably, the base is triethylamine.
Preferably, the amount of the base used is 1.0 to 2.0 times the amount of the substance of the N-phenacyl pyridinium bromide salt represented by the formula (1).
Preferably, the organic solvent is 1, 4-dioxane.
Preferably, the amount of the organic solvent used is 4 to 6mL/mmol as the substance of N-phenacyl pyridinium bromide represented by formula (1).
Preferably, the developing solvent used for the TLC tracing reaction is petroleum ether: ethyl acetate 10:1, V/V.
Further, the reaction liquid post-treatment method comprises the following steps: after the reaction is finished, pouring the reaction liquid into a round-bottom flask, carrying out reduced pressure distillation, then carrying out silica gel column chromatography separation, and carrying out reduced pressure distillation and drying on the obtained eluent to obtain the 1, 2-substituted indolizine compound shown in the formula (3).
Preferably, the eluent of the silica gel column chromatography is petroleum ether: ethyl acetate 15:1, V/V.
The method takes the metal silver salt as the catalyst, is prepared by a one-pot method, is simple to operate, the isocyanide compound and the N-phenacyl pyridinium bromide are two common and easily-obtained chemical raw materials, the raw materials and the reagents are easily obtained, the reaction condition is mild, the reaction system is green and environment-friendly, the product is easily separated and purified, the yield is up to 91 percent, and the method is suitable for preparing the indolizine compound with high efficiency and high yield, and is particularly suitable for synthesizing various 1, 2-substituted indolizine compounds. The invention is suitable for large-scale industrial production, and has wide application prospect and important significance in organic synthesis.
Drawings
FIG. 1 is a drawing of indolizine 3a prepared in example 11Nuclear magnetic resonance spectrum of H-NMR;
FIG. 2 is a photograph of indolizine 3a prepared in example 113Nuclear magnetic resonance spectrum of C-NMR;
FIG. 3 is a photograph of indolizine 3b prepared in example 21Nuclear magnetic resonance spectrum of H-NMR;
FIG. 4 is a depiction of indolizine 3b prepared in example 213Nuclear magnetic resonance spectrum of C-NMR;
FIG. 5 is a photograph of indolizine 3d prepared in example 41Nuclear magnetic resonance spectrum of H-NMR;
FIG. 6 is a depiction of indolizine 3d prepared in example 413Nuclear magnetic resonance spectrum of C-NMR;
FIG. 7 shows 3g of indolizine prepared in example 71Nuclear magnetic resonance spectrum of H-NMR;
FIG. 8 is a graph of 3g of indolizine prepared in example 713Nuclear magnetic resonance spectrum of C-NMR;
FIG. 9 is a depiction of indolizine 3j prepared in example 101Nuclear magnetic resonance spectrum of H-NMR;
FIG. 10 is a photograph of indolizine 3j prepared in example 1013Nuclear magnetic resonance spectrum of C-NMR.
Detailed Description
The invention is described in further detail below with reference to the figures and specific examples.
Example 1: preparation of indolizine derivative 3a
To a 10mL pressure resistant tube equipped with a magnetic stirring apparatus were added N-phenacyl bromopyridine 1a (0.139g,0.5mmol), silver carbonate (0.207g,0.75mmol), triethylamine (104. mu.L, 0.75mmol), 1, 4-dioxane (3mL) and ethyl isocyanate 2a (66. mu.L, 0.6mmol), and stirred at 20 ℃ for 2 h. TLC (developing solvent V)Petroleum ether:VEthyl acetate10:1) detection of substrate disappearance and reaction end. Pouring the reaction solution into a round-bottom flask, distilling under reduced pressure, and performing silica gel column chromatography (eluent is V)Petroleum ether:VEthyl acetateSeparation was performed at 15:1), and the obtained eluent was distilled under reduced pressure and dried to obtain a white solid, which was confirmed to be the indolizine derivative 3a by NMR and MS, with the yield of 88%.
The detection of hydrogen spectrum, carbon spectrum and high resolution mass spectrum is carried out on the indolizine derivative 3a, the spectrogram is shown in figures 1 and 2, and the analytical data are as follows:
white solid, melting point 117-;1H NMR(400MHz,CDCl3):δH8.24(d, J ═ 9.2Hz,1H),7.98(d, J ═ 6.8Hz,1H),7.53 to 7.50(m,2H),7.41 to 7.33(m,3H),7.25(s,1H),7.09 to 7.04(m,1H),6.74 to 6.71(m,1H),4.25(q, J ═ 7.2Hz,2H),1.23(t, J ═ 7.2Hz,3H) (fig. 1);13C NMR(100MHz,CDCl3):δC165.0,136.7,134.9,132.7,129.9,127.5,127.0,125.5,122.4,120.3,113.7,112.6,101.5,59.3,14.3 (FIG. 2); HRMS (ESI-TOF, m/z): Calcd for C17H15NNaO2[M+Na]+288.0995 and found 288.0989. These parameters correspond to the chemical structure of the inventive compounds.
Example 2:
indolizine derivative 3b was prepared by substituting 1b for 1a in example 1.
To a magnetic stirring deviceTo 10mL of the pressure resistant tube were added N-phenacylbromopyridine 1b (0.148g,0.5mmol), silver carbonate (0.276g,1.0mmol), potassium carbonate (0.104g,0.75mmol), 1, 4-dioxane (3mL) and ethyl isocyanate 2a (66. mu.L, 0.6mmol), and the mixture was stirred at 20 ℃ for 2 hours. TLC (developing solvent V)Petroleum ether:VEthyl acetate10:1) detection of substrate disappearance and reaction end. Pouring the reaction solution into a round-bottom flask, distilling under reduced pressure, and performing silica gel column chromatography (eluent is V)Petroleum ether:VEthyl acetateSeparation was performed at 15:1), and the obtained eluent was distilled under reduced pressure and dried to obtain a white solid, which was confirmed to be the indolizine derivative 3b by NMR and MS, with the yield of 86%.
The indolizine derivative 3b is subjected to hydrogen spectrum, carbon spectrum and high-resolution mass spectrum detection, the spectrograms are shown in figures 3 and 4, and the analytical data are as follows:
white solid, melting point 126-;1H NMR(400MHz,CDCl3):δH8.23(d, J ═ 8.8Hz,1H),7.98(d, J ═ 6.8Hz,1H),7.49-7.54(m,2H),7.22(s,1H),7.10-7.05(m,3H),6.75-6.72(m,1H),4.26(q, J ═ 7.2Hz,2H),1.25(t, J ═ 7.2Hz,3H) (fig. 3);13C NMR(100MHz,CDCl3):δC164.9,162.2(d,JF-C＝244.0Hz),136.7,131.7,131.5(d,JF-C＝7.9Hz),130.9(d,JF-C＝3.3Hz),125.5,122.6,120.4,114.4(d,JF-C21.2Hz),113.6,112.7,101.5,59.4,14.3 (fig. 4); HRMS (ESI-TOF, m/z): Calcd for C17H14FNNaO2[M+Na]+306.0901 and found 306.0908. These parameters correspond to the chemical structure of the inventive compounds.
Example 3:
indolizine derivative 3c was prepared by substituting 1c for 1a in example 1.
To a 10mL pressure tube equipped with a magnetic stirring apparatus were added N-phenacyl bromopyridine 1c (0.156g,0.5mmol), silver carbonate (0.207g,0.75mmol), triethylamine (104. mu.L, 0.75mmol), 1, 2-dichloroethane (2mL) and ethyl isocyanate 2a(66. mu.L, 0.6mmol) and stirred at 20 ℃ for 2 h. TLC (developing solvent V)Petroleum ether:VEthyl acetate10:1) detection of substrate disappearance and reaction end. Pouring the reaction solution into a round-bottom flask, distilling under reduced pressure, and performing silica gel column chromatography (eluent is V)Petroleum ether:VEthyl acetateSeparation was performed at 15:1), and the obtained eluent was distilled under reduced pressure and dried to obtain a white solid, which was confirmed to be the indolizine derivative 3c by NMR and MS, with the yield of 91%.
The hydrogen spectrum, the carbon spectrum and the high-resolution mass spectrum detection are carried out on the indolizine derivative 3c, and the spectrogram analysis data is as follows:
white solid, melting point 109-;1H NMR(400MHz,CDCl3):δH 8.24(d,J＝9.2Hz,1H),7.99(d,J＝7.2Hz,1H),7.45(d,J＝8.4Hz,2H),7.36(d,J＝8.4Hz,2H),7.24(s,1H),7.10-7.06(m,1H),6.76-6.73(m,1H),4.27(q,J＝7.2Hz,2H),1.26(t,J＝7.2Hz,3H)；13C NMR(100MHz,CDCl3):δC 164.8,136.8,133.4,133.1,131.5,131.2,1277,125.5,122.6,120.4,113.6,112.8,101.5,59.4,14.3；HRMS(ESI-TOF,m/z):Calcd for C17H14ClNNaO2[M+Na]+322.0605 and found 322.0608. These parameters correspond to the chemical structure of the inventive compounds.
Example 4:
indolizine derivative 3d was prepared by substituting 1d for 1a in example 1.
To a 10mL pressure resistant tube equipped with a magnetic stirring apparatus were added N-phenacyl bromopyridine 1d (0.179g,0.5mmol), silver triflate (0.193g,0.75mmol), triethylamine (104. mu.L, 0.75mmol), acetonitrile (3mL) and ethyl isocyanate 2a (66. mu.L, 0.6mmol), and stirred at 20 ℃ for 2 h. TLC (developing solvent V)Petroleum ether:VEthyl acetate10:1) detection of substrate disappearance and reaction end. Pouring the reaction solution into a round-bottom flask, distilling under reduced pressure, and performing silica gel column chromatography (eluent is V)Petroleum ether:VEthyl acetate15:1) of the separation of the two fractions,the obtained eluate was distilled under reduced pressure and dried to obtain a white solid, which was confirmed to be the indolizine derivative 3d by NMR and MS, and the yield thereof was 87%.
The detection of hydrogen spectrum, carbon spectrum and high resolution mass spectrum is carried out on the indolizine derivative 3d, the spectrogram is shown in fig. 5 and 6, and the analytical data are as follows:
white solid, melting point 124-;1H NMR(400MHz,CDCl3):δH8.23(d, J ═ 9.2Hz,1H),7.98(d, J ═ 6.8Hz,1H),7.51(d, J ═ 8.4Hz,2H),7.38(d, J ═ 8.4Hz,2H),7.23(s,1H),7.08(dd, J ═ 6.8Hz, J' ═ 9.2Hz,1H),6.76-6.72(m,1H),4.27(q, J ═ 7.2Hz,2H),1.26(t, J ═ 7.2Hz,3H) (fig. 5);13C NMR(100MHz,CDCl3):δC164.8,136.8,133.9,131.54,131.39,130.7,125.5,122.7,121.3,120.4,113.6,112.8,101.4,59.4,14.3 (FIG. 6); HRMS (ESI-TOF, m/z): Calcd for C17H14BrNNaO2[M+Na]+366.0100 and found 366.0105. These parameters correspond to the chemical structure of the inventive compounds.
Example 5:
indolizine derivative 3e was prepared by substituting 1e for 1a in example 1.
N-phenacyl bromopyridine 1e (0.162g,0.5mmol), silver fluoride (0.163g,0.75mmol), triethylamine (138. mu.L, 1.0mmol), 1, 4-dioxane (3mL) and ethyl isocyanate 2a (83. mu.L, 0.75mmol) were added to a 10mL pressure resistant tube with a magnetic stirring apparatus, and stirred at 20 ℃ for 2 h. TLC (developing solvent V)Petroleum ether:VEthyl acetate10:1) detection of substrate disappearance and reaction end. Pouring the reaction solution into a round-bottom flask, distilling under reduced pressure, and performing silica gel column chromatography (eluent is V)Petroleum ether:VEthyl acetateSeparation was performed at 15:1), and the obtained eluent was distilled under reduced pressure and dried to obtain a white solid, which was confirmed to be indolizine derivative 3e by NMR and MS, with the yield of 91%.
The hydrogen spectrum, the carbon spectrum and the high-resolution mass spectrum detection are carried out on the indolizine derivative 3e, and the spectrogram analysis data is as follows:
yellow solid, melting point 153-;1H NMR(400MHz,CDCl3):δH 8.26-8.24(m,3H),8.02(d,J＝7.2Hz,1H),7.68(d,J＝8.4Hz,2H),7.31(s,1H),7.12(dd,J＝6.8Hz,J’＝9.2Hz,1H),4.28(q,J＝7.2Hz,2H),1.26(t,J＝7.2Hz,3H)；13C NMR(100MHz,CDCl3):δC 164.5,146.9,142.1,137.0,130.7,130.4,125.7,123.2,122.8,120.5,114.0,113.2,101.5,59.4,14.3；HRMS(ESI-TOF,m/z):Calcd for C17H14N2NaO2[M+Na]+333.0846 and found 333.0852. These parameters correspond to the chemical structure of the inventive compounds.
Example 6:
indolizine derivative 3f was prepared by substituting 1f for 1a in example 1.
N-phenacyl bromopyridine 1f (0.146g,0.5mmol), silver oxide (0.174g,0.75mmol), triethylamine (104. mu.L, 0.75mmol), N-dimethylformamide (3mL) and ethyl isocyanate 2a (83. mu.L, 0.75mmol) were added to a 10mL pressure resistant tube with a magnetic stirring apparatus, and stirred at 20 ℃ for 2 h. TLC (developing solvent V)Petroleum ether:VEthyl acetate10:1) detection of substrate disappearance and reaction end. Pouring the reaction solution into a round-bottom flask, distilling under reduced pressure, and performing silica gel column chromatography (eluent is V)Petroleum ether:VEthyl acetateSeparation was performed at 15:1), and the obtained eluent was distilled under reduced pressure and dried to obtain a white solid, which was confirmed to be the indolizine derivative 3f by NMR and MS, with the yield of 81%.
The hydrogen spectrum, the carbon spectrum and the high-resolution mass spectrum detection are carried out on the indolizine derivative 3f, and the spectrogram analysis data is as follows:
white solid, melting point 115-;1H NMR(400MHz,CDCl3):δH 8.22(d,J＝9.2Hz,1H),7.96(d,J＝6.8Hz,1H),7.41(d,J＝8.0Hz,2H),7.22(s,1H),7.20(d,J＝8.0Hz,2H),7.07-7.03(m,1H),6.72-6.69(m,1H),4.27(q,J＝7.2Hz,2H),2.39(s,3H),1.26(t,J＝7.2Hz,3H)；13C NMR(100MHz,CDCl3):δC 165.0,136.7,132.8,131.9,129.8,128.3,125.5,122.3,120.3,113.6,112.5,101.5,59.4,21.2,14.3；HRMS(ESI-TOF,m/z):Calcd for C18H17NNaO5[M+Na]+302.1151 and found 302.1158. These parameters correspond to the chemical structure of the inventive compounds.
Example 7:
indolizine derivatives (3 g) were prepared by substituting 1g for 1a in example 1.
To a 10mL pressure resistant tube equipped with a magnetic stirring apparatus were added 1g (0.177g,0.5mmol) of N-phenacyl bromopyridine, 0.125g,0.75mmol of silver acetate, 0.245g,0.75mmol of cesium carbonate, 3mL of 1, 4-dioxane, and ethyl isocyanate 2a (110. mu.L, 1.0mmol), and stirred at 20 ℃ for 2 h. TLC (developing solvent V)Petroleum ether:VEthyl acetate10:1) detection of substrate disappearance and reaction end. Pouring the reaction solution into a round-bottom flask, distilling under reduced pressure, and performing silica gel column chromatography (eluent is V)Petroleum ether:VEthyl acetateSeparation was performed at 15:1), and the obtained eluent was distilled under reduced pressure and dried to obtain a white solid, which was confirmed to be a indolizine derivative 3g by NMR and MS, with the yield of 78%.
The detection of 3g of indolizine derivative by hydrogen spectrum, carbon spectrum and high resolution mass spectrum is carried out, the spectrogram is shown in fig. 7 and 8, and the analytical data are as follows:
white solid, melting point 197-;1H NMR(400MHz,CDCl3):δH8.25(d, J ═ 9.2Hz,1H),7.99(d, J ═ 6.8Hz,1H),7.66-7.59(m,6H),7.47-7.44(m,2H),7.37-7.33(m,1H),7.29(s,1H),7.09-7.05(m,1H),6.75-6.71(m,1H),4.29(q, J ═ 7.2Hz,2H),1.27(t, J ═ 7.2Hz,3H) (fig. 7);13C NMR(100MHz,CDCl3):δC165.0,141.1,139.9,136.9,134.0,132.4,130.3,128.8,127.2,127.1,126.3,125.5,122.5,120.4,113.7,112.7,101.6,59.4,14.4 (FIG. 8); HRMS (ESI-TOF, m/z): Calcd for C23H19NNaO2[M+Na]+364.1308 and found 364.1321. These parameters correspond to the chemical structure of the inventive compounds.
Example 8:
indolizine derivatives 3h were prepared substituting 1h for 1a in example 1.
N-phenacyl bromopyridine (N-phenacyl bromopyridine) (0.174g,0.5mmol), silver carbonate (0.207g,0.75mmol), triethylamine (69. mu.L, 0.5mmol), 1, 4-dioxane (3mL) and ethyl isocyanate 2a (66. mu.L, 0.6mmol) were added to a 10mL pressure resistant tube with a magnetic stirring apparatus, and stirred at 20 ℃ for 2 h. TLC (developing solvent V)Petroleum ether:VEthyl acetate10:1) detection of substrate disappearance and reaction end. Pouring the reaction solution into a round-bottom flask, distilling under reduced pressure, and performing silica gel column chromatography (eluent is V)Petroleum ether:VEthyl acetateSeparation is carried out at a ratio of 15:1), and the obtained eluent is distilled and dried under reduced pressure to obtain a white solid which is confirmed to be the indolizine derivative by NMR and MS for 3h, and the yield is 85%.
The hydrogen spectrum, the carbon spectrum and the high-resolution mass spectrum detection are carried out on the indolizine derivative for 3h, and the spectrogram analysis data is as follows:
white solid, melting point 105-;1H NMR(400MHz,CDCl3):δH 8.25(d,J＝9.2Hz,1H),7.99(d,J＝6.8Hz,1H),7.61(d,J＝2.0Hz,1H),7.45(d,J＝8.0Hz,1H),7.36(dd,J＝8.4Hz,J’＝2.0Hz,1H),7.24(s,1H),7.10(dd,J＝6.8Hz,J’＝8.8Hz,1H),6.78-6.74(m,1H),4.27(q,J＝7.2Hz,2H),1.27(t,J＝7.2Hz,3H)；13C NMR(100MHz,CDCl3):δC 165.7,136.9,135.1,131.7,131.5,131.1,130.1,129.43,129.40,125.6,122.9,120.5,113.7,113.0,101.4,59.5,14.3；HRMS(ESI-TOF,m/z):Calcd for C17H13Cl2NNaO2[M+Na]+356.0216 and found 356.0223. These parameters correspond to the chemical structure of the inventive compounds.
Example 9:
indolizine derivatives 3i were prepared by substituting 1i for 1a in example 1.
N-phenacyl bromopyridine 1i (0.164g,0.5mmol), silver tetrafluoroborate (0.97g,0.5mmol), triethylamine (104. mu.L, 0.75mmol), tetrahydrofuran (3mL) and ethyl isocyanate 2a (66. mu.L, 0.6mmol) were added to a 10mL pressure resistant tube with a magnetic stirring apparatus and stirred at 20 ℃ for 2 h. TLC (developing solvent V)Petroleum ether:VEthyl acetate10:1) detection of substrate disappearance and reaction end. Pouring the reaction solution into a round-bottom flask, distilling under reduced pressure, and performing silica gel column chromatography (eluent is V)Petroleum ether:VEthyl acetateSeparation was performed at 15:1), and the obtained eluent was distilled under reduced pressure and dried to obtain a white solid, which was confirmed to be an indolizine derivative 3i by NMR and MS, with a yield of 91%.
The hydrogen spectrum, the carbon spectrum and the high-resolution mass spectrum detection are carried out on the indolizine derivative 3i, and the spectrogram analysis data is as follows:
white solid, melting point 117-;1H NMR(400MHz,CDCl3):δH 8.21(d,J＝9.6Hz,1H),7.91(d,J＝8.4Hz,1H),7.78(s,1H),7.74(d,J＝8.0Hz,1H),7.60-7.54(m,3H),7.43-7.33(m,5H),4.27(q,J＝7.2Hz,2H),1.23(t,J＝7.2Hz,3H)；13C NMR(100MHz,CDCl3):δC 165.1,135.2,134.9,132.3,131.3,129.9,128.9,128.8,127.6,127.0,124.6,124.0,123.6,118.9,114.5,112.4,105.2,59.6,14.2；HRMS(ESI-TOF,m/z):Calcd for C21H17NNaO2[M+Na]+338.1151 and found 338.1153. These parameters correspond to the chemical structure of the inventive compounds.
Example 10:
indolizine derivative 3j was prepared by substituting 2b for 2a in example 1.
To a 10mL pressure resistant tube equipped with a magnetic stirring apparatus were added N-phenacyl bromopyridine 1a (0.139g,0.5mmol), silver carbonate (0.207g,0.75mmol), DBU (112. mu.L, 0.75mmol), 1, 4-dioxane (3mL) and methyl isocyanurate 2b (91. mu.L, 1.0mmol), and stirred at 20 ℃ for 2 h. TLC (developing solvent V)Petroleum ether:VEthyl acetate10:1) detection of substrate disappearance and reaction end. Pouring the reaction solution into a round-bottom flask, distilling under reduced pressure, and performing silica gel column chromatography (eluent is V)Petroleum ether:VEthyl acetateSeparation was performed at 15:1), and the obtained eluent was distilled under reduced pressure and dried to obtain a white solid, which was confirmed to be an indolizine derivative 3j by NMR and MS, with the yield being 88%.
The detection of hydrogen spectrum, carbon spectrum and high resolution mass spectrum is carried out on the indolizine derivative 3j, the spectrogram is shown in fig. 9 and fig. 10, and the analytical data are as follows:
white solid, melting point 91-92 deg.C;1H NMR(400MHz,CDCl3):δH8.23(d, J ═ 9.2Hz,1H),7.98(d, J ═ 6.8Hz,1H),7.51(d, J ═ 7.2Hz,2H),7.42-7.38(m,2H),7.36-7.32(m,1H),7.25(s,1H),7.09-7.05(m,1H),3.77(s,3H) (fig. 9);13C NMR(100MHz,CDCl3):δC165.4,136.8,134.9,132.8,129.8,127.7,127.1,125.6,122.5,120.4,113.8,112.7,101.3,50.6 (FIG. 10); HRMS (ESI-TOF, m/z): Calcd for C16H13NNaO2[M+Na]+274.0838 and found 274.0844. These parameters correspond to the chemical structure of the inventive compounds.
Example 11:
indolizine derivative 3a was prepared by substituting dimethyl sulfoxide for 1, 4-dioxane in example 1.
N-phenacyl bromopyridine 1a (0.139g,0.5mmol), silver carbonate (0.207g,0.75mmol), triethylamine (104. mu.L, 0.75mmol), dimethyl sulfoxide (3mL) and ethyl isocyanate 2a (66. mu.L, 0.6mmol) were added to a 10mL pressure resistant tube with a magnetic stirring apparatus, and stirred at 20 ℃ for 2 h. TLC (developing solvent V)Petroleum productsEther compounds:VEthyl acetate10:1) detection of substrate disappearance and reaction end. Pouring the reaction solution into a round-bottom flask, distilling under reduced pressure, and performing silica gel column chromatography (eluent is V)Petroleum ether:VEthyl acetateSeparation was performed at 15:1), and the obtained eluent was distilled under reduced pressure and dried to obtain a white solid, which was confirmed to be the indolizine derivative 3a by NMR and MS, with the yield of 73%.
Example 12:
indolizine derivative 3a was prepared by substituting toluene for 1, 4-dioxane in example 1.
N-phenacyl bromopyridine 1a (0.139g,0.5mmol), silver carbonate (0.207g,0.75mmol), triethylamine (104. mu.L, 0.75mmol), toluene (3mL) and ethyl isocyanate 2a (66. mu.L, 0.6mmol) were added to a 10mL pressure resistant tube with a magnetic stirring apparatus and stirred at 20 ℃ for 2 h. TLC (developing solvent V)Petroleum ether:VEthyl acetate10:1) detection of substrate disappearance and reaction end. Pouring the reaction solution into a round-bottom flask, distilling under reduced pressure, and performing silica gel column chromatography (eluent is V)Petroleum ether:VEthyl acetateSeparation was performed at 15:1), and the obtained eluent was distilled under reduced pressure and dried to obtain a white solid, which was confirmed to be the indolizine derivative 3a by NMR and MS, with the yield of 64%.
Example 13:
indolizine derivative 3a was prepared by substituting silver nitrate for silver carbonate in example 1.
N-phenacyl bromopyridine 1a (0.139g,0.5mmol), silver nitrate (0.127g,0.75mmol), triethylamine (104. mu.L, 0.75mmol), 1, 4-dioxane (3mL) and ethyl isocyanate 2a (66. mu.L, 0.6mmol) were added to a 10mL pressure resistant tube with a magnetic stirring apparatus, and stirred at 20 ℃ for 2 h. TLC (developing solvent V)Petroleum ether:VEthyl acetate＝10:1) detecting the disappearance of the substrate and finishing the reaction. Pouring the reaction solution into a round-bottom flask, distilling under reduced pressure, and performing silica gel column chromatography (eluent is V)Petroleum ether:VEthyl acetateSeparation was performed at 15:1), and the obtained eluent was distilled under reduced pressure and dried to obtain a white solid, which was confirmed to be the indolizine derivative 3a by NMR and MS, with the yield of 74%.
Example 14:
indolizine derivative 3a was prepared by substituting silver nitrite for silver carbonate in example 1.
N-phenacyl bromopyridine 1a (0.139g,0.5mmol), silver nitrite (0.115g,0.75mmol), triethylamine (104. mu.L, 0.75mmol), 1, 4-dioxane (3mL) and ethyl isocyanate 2a (66. mu.L, 0.6mmol) were added to a 10mL pressure resistant tube with a magnetic stirring apparatus, and stirred at 20 ℃ for 2 h. TLC (developing solvent V)Petroleum ether:VEthyl acetate10:1) detection of substrate disappearance and reaction end. Pouring the reaction solution into a round-bottom flask, distilling under reduced pressure, and performing silica gel column chromatography (eluent is V)Petroleum ether:VEthyl acetateSeparation was performed at 15:1), and the obtained eluent was distilled under reduced pressure and dried to obtain a white solid, which was confirmed to be the indolizine derivative 3a by NMR and MS, with the yield of 78%.
Claims (10)
1. A method for synthesizing indolizine compounds under the catalysis of silver is characterized in that N-phenacyl pyridinium bromide shown in a formula (1) and isocyanides shown in a formula (2) are used as raw materials in an organic solvent system, a metal silver salt is used as a catalyst, the raw materials are stirred and reacted in the air under the alkaline condition, tracking detection is carried out by TLC until the reaction is complete, and the indolizine compounds shown in a formula (3) are obtained after post-treatment of reaction liquid;
the organic solvent is one of 1, 2-dichloroethane, 1, 4-dioxane, N-dimethylformamide, acetonitrile, dimethyl sulfoxide, toluene and tetrahydrofuran;
the metal silver salt is one of silver carbonate, silver nitrate, silver oxide, silver fluoride, silver nitrite, silver acetate, silver trifluoromethanesulfonate and silver tetrafluoroborate;
the alkali is one of potassium carbonate, cesium carbonate, triethylamine and DBU;
the feeding molar ratio of the N-phenacyl pyridinium bromide to the isocyanic compounds is 1: (1.2-2.0);
wherein R is1Is hydrogen, phenyl, alkyl, alkoxy, nitro or halogen atom, R2Is methyl or ethyl.
2. The method for synthesizing indolizine compounds under the catalysis of silver as claimed in claim 1, wherein the metal silver salt is silver carbonate.
3. The method for synthesizing indolizine compounds under the catalysis of silver as claimed in claim 1 or 2, wherein the amount of the metal silver salt is 1.0-2.0 times of the amount of the N-phenacyl pyridinium bromide represented by formula (1).
4. The method for synthesizing indolizine compounds under the catalysis of silver as claimed in claim 1 or 2, wherein the base is triethylamine.
5. The method for synthesizing indolizine compounds under the catalysis of silver as claimed in claim 1 or 2, wherein the amount of the base is 1.0-2.0 times of the amount of the N-phenacyl pyridinium bromide represented by formula (1).
6. The method for synthesizing indolizine compounds under the catalysis of silver as claimed in claim 1 or 2, wherein the organic solvent is 1, 4-dioxane.
7. The method for synthesizing indolizine compounds under the catalysis of silver as claimed in claim 1 or 2, wherein the amount of the organic solvent is 4-6mL/mmol based on the substance of N-phenacyl pyridinium bromide represented by formula (1).
8. The method for synthesizing indolizine compounds with silver catalysis according to claim 1 or 2, wherein the developing agent used for TLC tracing reaction is petroleum ether: ethyl acetate 10:1, V/V.
9. The method for synthesizing indolizine compounds under the catalysis of silver according to claim 1 or 2, characterized in that the method for post-treating the reaction liquid is as follows: after the reaction is finished, pouring the reaction liquid into a round-bottom flask, carrying out reduced pressure distillation, then carrying out silica gel column chromatography separation, and carrying out reduced pressure distillation and drying on the obtained eluent to obtain the indolizine compound shown in the formula (3).
10. The method for synthesizing indolizine compounds under the catalysis of silver according to claim 9, wherein the eluent of the silica gel column chromatography is petroleum ether: ethyl acetate 15:1, V/V.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2010027762A1 (en) * | 2008-09-04 | 2010-03-11 | Boehringer Ingelheim International Gmbh | Indolizine inhibitors of leukotriene production |
| CN105801576A (en) * | 2016-04-12 | 2016-07-27 | 湖北科技学院 | Synthetic method of indolizine compounds |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2010027762A1 (en) * | 2008-09-04 | 2010-03-11 | Boehringer Ingelheim International Gmbh | Indolizine inhibitors of leukotriene production |
| CN105801576A (en) * | 2016-04-12 | 2016-07-27 | 湖北科技学院 | Synthetic method of indolizine compounds |
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| Title |
|---|
| DONG ZHANG 等: "Diversified Transformations of Tetrahydroindolizines to Construct Chiral 3-Arylindolizines and Dicarbofunctionalized 1,5-Diketones", 《JOURNAL OF THE AMERICAN CHEMICAL SOCIETY》 * |
| GUIZHOU YUE 等: "Synthesis of a library of 1,2,3,7-tetrasubstituted indolizines using poly(ethylene glycol) as soluble support", 《JOURNAL OF HETEROCYCLIC CHEMISTRY》 * |
| TAO GAO 等: "General and direct synthesis of indolizine-1-carbaldehydes by 1,3-dipolar cycloaddition of phenylpropiolaldehyde with pyridinium ylides", 《EUROPEAN JOURNAL OF ORGANIC CHEMISTRY 》 * |
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