CN113200980B - 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) with metallic silverAnd (3) taking salt as a catalyst, stirring in air for reaction under an alkaline condition, tracking and detecting by TLC until the reaction is complete, and carrying out aftertreatment on a 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 through silver catalysis.
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. The indolizine derivative has unique biological and pharmacological activities of resisting virus, bacteria, inflammation, hypertension, tumors and the like, so the indolizine derivative has wide application in the fields of medicines, pesticides, biology and the like. For example, swainsonine (Swainsonine) inhibits α -mannosidase II in the Golgi complex and thus inhibits the synthesis of N-linked oligosaccharides 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 structure, has good anti-tumor and anti-virus 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 is 1 Is hydrogen, phenyl, alkyl, alkoxy, nitro or halogen atom, R 2 Is 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 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 is 4-6mL/mmol based on the amount of the N-phenacyl pyridinium bromide represented by the formula (1).
Preferably, the developing solvent used for TLC follow-up 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 photograph of indolizine 3a prepared in example 1 1 Nuclear magnetic resonance spectrum by H-NMR;
FIG. 2 is a photograph of indolizine 3a prepared in example 1 13 Nuclear magnetic resonance spectrum by C-NMR;
FIG. 3 is a photograph of indolizine 3b prepared in example 2 1 Nuclear magnetic resonance spectrum of H-NMR;
FIG. 4 shows an embodimentPreparation of indolizine 3b of example 2 13 Nuclear magnetic resonance spectrum of C-NMR;
FIG. 5 is a photograph of indolizine 3d prepared in example 4 1 Nuclear magnetic resonance spectrum by H-NMR;
FIG. 6 is a depiction of indolizine 3d prepared in example 4 13 Nuclear magnetic resonance spectrum of C-NMR;
FIG. 7 shows 3g of indolizine prepared in example 7 1 Nuclear magnetic resonance spectrum by H-NMR;
FIG. 8 shows 3g of indolizine prepared in example 7 13 Nuclear magnetic resonance spectrum of C-NMR;
FIG. 9 is a depiction of indolizine 3j prepared in example 10 1 Nuclear magnetic resonance spectrum by H-NMR;
FIG. 10 is a photograph of indolizine 3j prepared in example 10 13 Nuclear magnetic resonance spectrum by 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
N-phenacyl bromopyridine 1a (0.139g, 0.5 mmol), silver carbonate (0.207g, 0.75mmol), triethylamine (104. Mu.L, 0.75 mmol), 1, 4-dioxane (3 mL) and ethyl isocyanate 2a (66. Mu.L, 0.6 mmol) were added to a 10mL pressure resistant tube with a magnetic stirring apparatus, and stirred at 20 ℃ for 2h. TLC (developing solvent V) Petroleum ether :V Ethyl acetate = 10). Pouring the reaction solution into a round-bottom flask, distilling under reduced pressure, and performing silica gel column chromatography (eluent is V) Petroleum ether :V Acetic acid ethyl ester = 15) separation, and the resulting eluate 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, and the yield thereof was 88%.
The indolizine derivative 3a is detected by hydrogen spectrum, carbon spectrum and high-resolution mass spectrum, the spectrograms are shown in figures 1 and 2, and analytical data are as follows:
white solidBulk, melting point 117-118 ℃; 1 H NMR(400MHz,CDCl 3 ):δ H 8.24 (d, J =9.2hz, 1h), 7.98 (d, J =6.8hz, 1h), 7.53-7.50 (m, 2H), 7.41-7.33 (m, 3H), 7.25 (s, 1H), 7.09-7.04 (m, 1H), 6.74-6.71 (m, 1H), 4.25 (q, J =7.2hz, 2h), 1.23 (t, J =7.2hz, 3h) (fig. 1); 13 C NMR(100MHz,CDCl 3 ):δ C 165.0,136.7,134.9,132.7,129.9,127.5,127.0,125.5,122.4,120.3,113.7,112.6,101.5,59.3,14.3 (FIG. 2); HRMS (ESI-TOF, m/z): calcd for C 17 H 15 NNaO 2 [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.
N-phenacyl bromopyridine 1b (0.148g, 0.5 mmol), silver carbonate (0.276g, 1.0 mmol), potassium carbonate (0.104g, 0.75mmol), 1, 4-dioxane (3 mL) and ethyl isocyanate 2a (66. Mu.L, 0.6 mmol) were added to a 10mL pressure resistant tube with a magnetic stirring apparatus, and stirred at 20 ℃ for 2h. TLC (developing solvent V) Petroleum ether :V Acetic acid ethyl ester = 10). Pouring the reaction solution into a round-bottom flask, distilling under reduced pressure, and performing silica gel column chromatography (eluent is V) Petroleum ether :V Ethyl acetate = 15) separation, and the obtained eluate 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, and the yield thereof was 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 126-127 ℃; 1 H NMR(400MHz,CDCl 3 ):δ H 8.23 (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); 13 C NMR(100MHz,CDCl 3 ):δ C 164.9,162.2(d,J F-C ＝244.0Hz),136.7,131.7,131.5(d,J F-C ＝7.9Hz),130.9(d,J F-C ＝3.3Hz),125.5,122.6,120.4,114.4(d,J F-C =21.2 Hz), 113.6,112.7,101.5,59.4,14.3 (fig. 4); HRMS (ESI-TOF, m/z): calcd for C 17 H 14 FNNaO 2 [M+Na] + 306.0901, 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.
N-phenacyl bromopyridine 1c (0.156g, 0.5 mmol), silver carbonate (0.207g, 0.75mmol), triethylamine (104. Mu.L, 0.75 mmol), 1, 2-dichloroethane (2 mL) and ethyl isocyanate 2a (66. Mu.L, 0.6 mmol) were added to a 10mL pressure resistant tube equipped with a magnetic stirring apparatus, and stirred at 20 ℃ for 2h. TLC (developing solvent is V) Petroleum ether :V Acetic acid ethyl ester = 10). Pouring the reaction solution into a round-bottom flask, distilling under reduced pressure, and performing silica gel column chromatography (eluent is V) Petroleum ether :V Ethyl acetate = 15) separation, and the obtained eluate 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, and the yield thereof was 91%.
By detecting the hydrogen spectrum, the carbon spectrum and the high-resolution mass spectrum of the indolizine derivative 3c, the spectrogram analysis data is as follows:
white solid, melting point 109-110 ℃; 1 H NMR(400MHz,CDCl 3 ):δ H 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)； 13 C NMR(100MHz,CDCl 3 ):δ C 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 C 17 H 14 ClNNaO 2 [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 stirrer was added N-phenacyl bromopyridine 1d (0.179g, 0.5 mmol), silver triflate (0.193g, 0.75mmol), triethylamine (104. Mu.L, 0.75 mmol), acetonitrile (3 mL) and ethyl isocyanate 2a (66. Mu.L, 0.6 mmol), and stirred at 20 ℃ for 2h. TLC (developing solvent is V) Petroleum ether :V Acetic acid ethyl ester = 10). Pouring the reaction solution into a round-bottom flask, distilling under reduced pressure, and performing silica gel column chromatography (eluent is V) Petroleum ether :V Acetic acid ethyl ester = 15) separation, and 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 indolizine derivative 3d is detected by hydrogen spectrum, carbon spectrum and high-resolution mass spectrum, the spectrograms are shown in figures 5 and 6, and the analytical data are as follows:
white solid, melting point 124-125 deg.C; 1 H NMR(400MHz,CDCl 3 ):δ H 8.23 (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); 13 C NMR(100MHz,CDCl 3 ):δ C 164.8,136.8,133.9,131.54,131.39,130.7,125.5,122.7,121.3,120.4,113.6,112.8,101.4,59.4,14.3 (FIG. 6); HRMS (ESI-TOF, m/z): calcd for C 17 H 14 BrNNaO 2 [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, 0.5 mmol), silver fluoride (0.163g, 0.75mmol), triethylamine (138. Mu.L, 1.0 mmol), 1, 4-dioxane (3 mL) and ethyl isocyanate 2a (83. Mu.L, 0.75 mmol) were added to a 10mL pressure resistant tube with a magnetic stirring apparatus, and stirred at 20 ℃ for 2h. TLC (developing solvent is V) Petroleum ether :V Ethyl acetate = 10). Pouring the reaction solution into a round-bottom flask, distilling under reduced pressure, and performing silica gel column chromatography (eluent is V) Petroleum ether :V Ethyl acetate = 15) separation, and the obtained eluate was distilled under reduced pressure and dried to obtain a white solid, which was confirmed to be the indolizine derivative 3e by NMR and MS, and the yield thereof was 91%.
By detecting the hydrogen spectrum, the carbon spectrum and the high-resolution mass spectrum of the indolizine derivative 3e, the spectrogram analysis data is as follows:
yellow solid, melting point 153-154 deg.C; 1 H NMR(400MHz,CDCl 3 ):δ H 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)； 13 C NMR(100MHz,CDCl 3 ):δ C 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 C 17 H 14 N 2 NaO 2 [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.
Adding into a 10mL pressure-resistant tube with a magnetic stirring deviceN-Benzylmethylbromopyridine 1f (0.146g, 0.5mmol), silver oxide (0.174g, 0.75mmol), triethylamine (104. Mu.L, 0.75 mmol), N-dimethylformamide (3 mL) and ethyl isocyanate 2a (83. Mu.L, 0.75 mmol), and stirred at 20 ℃ for 2h. TLC (developing solvent is V) Petroleum ether :V Acetic acid ethyl ester = 10). Pouring the reaction solution into a round-bottom flask, distilling under reduced pressure, and performing silica gel column chromatography (eluent is V) Petroleum ether :V Acetic acid ethyl ester = 15) separation, and the obtained eluate 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, and the yield thereof was 81%.
The method comprises the following steps of (1) detecting the indolizine derivative 3f by a hydrogen spectrum, a carbon spectrum and a high-resolution mass spectrum, wherein the spectrogram analysis data is as follows:
white solid, melting point 115-116 deg.C; 1 H NMR(400MHz,CDCl 3 ):δ H 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)； 13 C NMR(100MHz,CDCl 3 ):δ C 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 C 18 H 17 NNaO 5 [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, 0.24pg, 0.75mmol of cesium carbonate, 3mL of 1, 4-dioxane, and ethyl isocyanate 2a (110. Mu.L, 1.0 mmol), and stirred at 20 ℃ for 2h. TLC (developing solvent is V) Petroleum ether :V Acetic acid ethyl ester = 10)The reaction is ended. Pouring the reaction solution into a round-bottom flask, distilling under reduced pressure, and performing silica gel column chromatography (eluent is V) Petroleum ether :V Acetic acid ethyl ester = 15) separation, and the resulting eluate was distilled under reduced pressure and dried to obtain a white solid, which was confirmed to be an indolizine derivative 3g by NMR and MS, and the yield thereof was 78%.
The detection of hydrogen spectrum, carbon spectrum and high-resolution mass spectrum is carried out on 3g of the indolizine derivative, the spectrograms are shown in figures 7 and 8, and analytical data are as follows:
white solid, melting point 197-198 deg.C; 1 H NMR(400MHz,CDCl 3 ):δ H 8.25 (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); 13 C NMR(100MHz,CDCl 3 ):δ C 165.0,141.1,139.9,136.9,134.0,132.4,130.3,128.8,127.2,127.1,126.3,125.5,122.5,120.4,113.7,112.7,101.6,59.4,14.4 (FIG. 8); HRMS (ESI-TOF, m/z) Calcd for C 23 H 19 NNaO 2 [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, 0.5 mmol), silver carbonate (0.207g, 0.75mmol), triethylamine (69. Mu.L, 0.5 mmol), 1, 4-dioxane (3 mL) and ethyl isocyanate 2a (66. Mu.L, 0.6 mmol) were added to a 10mL pressure resistant tube with a magnetic stirring apparatus, and stirred at 20 ℃ for 2h. TLC (developing solvent V) Petroleum ether :V Ethyl acetate = 10). Pouring the reaction solution into a round-bottom flask, distilling under reduced pressure, and performing silica gel column chromatography (eluent is V) Petroleum ether :V Acetic acid ethyl ester = 15) separating, distilling the obtained eluent under reduced pressure, drying, obtaining a white solid which is obtained byNMR and MS prove that the intermediate is the indolizine derivative 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 105-106 ℃; 1 H NMR(400MHz,CDCl 3 ):δ H 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)； 13 C NMR(100MHz,CDCl 3 ):δ C 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 C 17 H 13 Cl 2 NNaO 2 [M+Na] + 356.0216, found 356.0223. These parameters correspond to the chemical structure of the inventive compounds.
Example 9:
indolizine derivative 3i was prepared by substituting 1i for 1a in example 1.
To a 10mL pressure resistant tube equipped with a magnetic stirring apparatus were added N-phenacyl bromopyridine 1i (0.164g, 0.5 mmol), silver tetrafluoroborate (0.97g, 0.5 mmol), triethylamine (104. Mu.L, 0.75 mmol), tetrahydrofuran (3 mL) and ethyl isocyanurate 2a (66. Mu.L, 0.6 mmol), and stirred at 20 ℃ for 2h. TLC (developing solvent is V) Petroleum ether :V Ethyl acetate = 10). Pouring the reaction solution into a round-bottom flask, distilling under reduced pressure, and performing silica gel column chromatography (eluent is V) Petroleum ether :V Ethyl acetate = 15) separation, and the resulting eluate 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, and the yield thereof was 91%.
By detecting the hydrogen spectrum, the carbon spectrum and the high-resolution mass spectrum of the indolizine derivative 3i, the spectrogram analysis data is as follows:
white solid, melting point 117-118 ℃; 1 H NMR(400MHz,CDCl 3 ):δ H 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)； 13 C NMR(100MHz,CDCl 3 ):δ C 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 C 21 H 17 NNaO 2 [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.
N-phenacyl bromopyridine 1a (0.139g, 0.5 mmol), silver carbonate (0.207g, 0.75mmol), DBU (112. Mu.L, 0.75 mmol), 1, 4-dioxane (3 mL) and methyl isocyanurate 2b (91. Mu.L, 1.0 mmol) were added to a 10mL pressure resistant tube with a magnetic stirring apparatus, and stirred at 20 ℃ for 2h. TLC (developing solvent V) Petroleum ether :V Acetic acid ethyl ester = 10). Pouring the reaction solution into a round-bottom flask, distilling under reduced pressure, and performing silica gel column chromatography (eluent is V) Petroleum ether :V Ethyl acetate = 15) separation, and the obtained eluate was distilled under reduced pressure and dried to obtain a white solid, which was confirmed to be the indolizine derivative 3j by NMR and MS, and the yield thereof was 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; 1 H NMR(400MHz,CDCl 3 ):δ H 8.23 (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); 13 C NMR(100MHz,CDCl 3 ):δ C 165.4,136.8,134.9,132.8,129.8,127.7,127.1,125.6,122.5,120.4,113.8,112.7,101.3,50.6 (FIG. 10); HRMS (ESI-TOF, m/z) Calcd for C 16 H 13 NNaO 2 [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 1, 4-dioxane in example 1 with dimethyl sulfoxide.
N-phenacyl bromopyridine 1a (0.139g, 0.5 mmol), silver carbonate (0.207g, 0.75mmol), triethylamine (104. Mu.L, 0.75 mmol), dimethyl sulfoxide (3 mL) and ethyl isocyanate 2a (66. Mu.L, 0.6 mmol) were added to a 10mL pressure resistant tube with a magnetic stirring apparatus, and stirred at 20 ℃ for 2h. TLC (developing solvent V) Petroleum ether :V Acetic acid ethyl ester = 10). Pouring the reaction solution into a round-bottom flask, distilling under reduced pressure, and performing silica gel column chromatography (eluent is V) Petroleum ether :V Acetic acid ethyl ester = 15) separation, and the obtained eluate 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, and the yield thereof was 73%.
Example 12:
indolizine derivative 3a was prepared by substituting toluene for 1, 4-dioxane in example 1.
N-phenacyl bromopyridine 1a (0.139g, 0.5 mmol), silver carbonate (0.207g, 0.75mmol), triethylamine (104. Mu.L, 0.75 mmol), toluene (3 mL) and ethyl isocyanate 2a (66. Mu.L, 0.6 mmol) were added to a 10mL pressure resistant tube with a magnetic stirring apparatus and stirred at 20 ℃ for 2h. TLC (developing solvent V) Petroleum ether :V Ethyl acetate = 10)And (6) ending. Pouring the reaction solution into a round-bottom flask, distilling under reduced pressure, and performing silica gel column chromatography (eluent is V) Petroleum ether :V Ethyl acetate = 15) separation, and the resulting eluate 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, and the yield thereof was 64%.
Example 13:
indolizine derivative 3a was prepared by substituting silver nitrate for silver carbonate in example 1.
N-phenacyl bromopyridine 1a (0.139g, 0.5 mmol), silver nitrate (0.127g, 0.75mmol), triethylamine (104. Mu.L, 0.75 mmol), 1, 4-dioxane (3 mL) and ethyl isocyanate 2a (66. Mu.L, 0.6 mmol) were added to a 10mL pressure resistant tube with a magnetic stirring apparatus, and stirred at 20 ℃ for 2h. TLC (developing solvent is V) Petroleum ether :V Ethyl acetate = 10). Pouring the reaction solution into a round-bottom flask, distilling under reduced pressure, and performing silica gel column chromatography (eluent is V) Petroleum ether :V Acetic acid ethyl ester = 15) separation, and the obtained eluate 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, and the yield thereof was 74%.
Example 14:
indolizine derivative 3a was prepared by substituting silver nitrite for silver carbonate in example 1.
N-benzoylmethyl bromopyridine 1a (0.139g, 0.5 mmol), silver nitrite (0.115g, 0.75mmol), triethylamine (104. Mu.L, 0.75 mmol), 1, 4-dioxane (3 mL), and ethyl isocyanate 2a (66. Mu.L, 0.6 mmol) were added to a 10mL pressure resistant tube equipped with a magnetic stirring apparatus, and stirred at 20 ℃ for 2h. TLC (developing solvent is V) Petroleum ether :V Acetic acid ethyl ester = 10). The reaction solution was poured intoDistilling under reduced pressure in a round-bottom flask, and performing silica gel column chromatography (eluent is V) Petroleum ether :V Ethyl acetate = 15) separation, and the obtained eluate 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, and the yield thereof was 78%.
Claims (10)
1. A method for synthesizing indolizine compounds under the catalysis of silver is characterized in that N-phenacyl pyridinium bromide and isocyanic compounds shown in a formula (2) are used as raw materials in an organic solvent system, metal silver salt is used as a catalyst, the raw materials are stirred in the air to react under the alkaline condition, the raw materials are stirred for 2 hours at the temperature of 20 ℃, tracking detection is carried out through TLC (thin layer chromatography) until the reaction is complete, and the indolizine compounds 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 used under the alkaline condition 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);
the structural formula of the isocyan compound shown in the formula (2) is shown as
Wherein R is 2 Is methyl or ethyl;
the structural formula of the N-phenacyl pyridinium bromide is one of formula 1a, formula 1b, formula 1c, formula 1d, formula 1e, formula 1f, formula 1g, formula 1h and formula 1i, and the structural formula of the corresponding indolizine compound is formula 3a or formula 3j, formula 3b, formula 3c, formula 3d, formula 3e, formula 3f, formula 3g, formula 3h and formula 3i;
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 silver-catalyzed synthesis of indolizines based on claim 1 or 2, wherein the amount of the metal silver salt is 1.0 to 2.0 times the amount of the substance of the N-phenacylpyridinium bromide represented by formula (1).
4. The method for silver-catalyzed synthesis of indolizines based on claim 1 or 2, wherein the base is triethylamine.
5. The method for silver-catalyzed synthesis of indolizines based on claim 1 or 2, wherein the amount of the base is 1.0 to 2.0 times of the amount of the substance of the N-phenacylpyridinium bromide represented by formula (1).
6. The method for silver-catalyzed synthesis of indolizine compounds according to 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, wherein the post-treatment method of the reaction solution 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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