A method for synthesizing 4-formylpyrrole derivatives by silver catalysis and its application

Abstract

A method and application of silver-catalyzed synthesis of 4-formylpyrrole derivatives, specifically comprising the following steps: adding an alkenyl nitrone compound of formula 1 and isocyanoacetate of formula 2 as reaction raw materials to an organic solvent, adding a base, adding argon protection under the catalysis of a metal silver salt, stirring the reaction at 80°C, tracking the reaction to completion by TLC, and treating the reaction solution to obtain a 4-formylpyrrole derivative of formula 3; the molar ratio between the alkenyl nitrone compound and the isocyanoacetate is 1:1; the molar ratio between the metal silver salt and the alkenyl nitrone compound is 1:5. The present invention is synthesized by a one-pot cycloaddition reaction, is simple to operate, has readily available reagents, mild reaction conditions, a green reaction system, is easy to separate and purify the product, has a high yield, and is suitable for synthesizing various highly functionalized 4-formylpyrrole derivatives; and it is confirmed by application that 4-formylpyrrole compounds can be converted into N-sulfonylated pyrrole compounds.

Description

Technical Field

[0001] The invention belongs to the field of organic chemical synthesis, and specifically relates to a method for synthesizing 4-formylpyrrole derivatives by using silver catalysis and application thereof. Background Art

[0002] Pyrrole is a very important class of organic compounds, which are widely present in drug molecules, natural products, pesticides and functional material molecules. It has a wide range of biological activities and medicinal value, so their preparation methods have always been one of the hot spots in organic synthesis research. Studies have shown that some pyrrole compounds have anti-tumor and antiviral effects. Compounds containing pyrrole and pyrrolidine skeletons are widely present in many drugs. For example, 10Z-Hymenialdisine is a natural biologically active pyrrole alkaloid. It is also a pan-kinase inhibitor with certain anticancer activity. Clindamycin is an antibiotic drug that can inhibit the synthesis of bacterial proteins by binding to ribosomes and exert antibacterial activity. In the field of pesticides, pyrrole compounds have certain insecticidal and fungicidal activities. For example, chlorfenapyr is an aromatic pyrrole nitrile insecticide and acaricide. As a representative of the recommended pesticide varieties for pest control of pollution-free agricultural products, it has an increasingly broad application field. Therefore, people are studying how to develop effective methods to synthesize pyrrole compounds.

[0003]

[0004] At present, the existing methods for synthesizing pyrrole still have some defects, such as: narrow substrate range, harsh reaction conditions, low product yield, etc., which do not meet the atom economy and lack practical value. Therefore, it is of great significance to develop and find a practical method for synthesizing 1-naphthylamine compounds. Summary of the invention

[0005] The present invention aims to provide a method for synthesizing 4-formylpyrrole derivatives by silver catalysis and application thereof. The method has the advantages of mild reaction process, simplicity, safety and easy operation, and high yield. The 4-formylpyrrole derivatives synthesized by the method can be further converted into N-sulfonylated pyrrole compounds.

[0006] To achieve the above object, the technical scheme adopted by the present invention is: a method for synthesizing 4-formylpyrrole derivatives catalyzed by silver, which specifically comprises the following steps: adding an alkenyl nitrone compound of formula 1 and an isocyanoacetate compound of formula 2 as reaction raw materials to an organic solvent, adding a base, adding argon protection under the catalysis of a metal silver salt, stirring the reaction at 80° C., tracking the reaction by TLC until the reaction is complete, and obtaining a 4-formylpyrrole derivative of a compound of formula 3 after treating the reaction solution;

[0007] Wherein, the molar ratio between the alkenyl nitrone compound and the isocyanoacetate is 1:1;

[0008] The molar ratio between the metal silver salt and the alkenyl nitrone compound is 1:5;

[0009] The organic solvent is one of 1,4-dioxane, N,N-dimethylformamide and dimethyl sulfoxide;

[0010] The base is one of cesium carbonate, potassium phosphate and potassium carbonate;

[0011] The metal silver salt is one of silver carbonate, silver oxide, silver trifluoromethanesulfonate and silver p-toluenesulfonate;

[0012] The structural formula of the alkenyl nitrone compound of Formula 1 is In formula 1, R 1 is hydrogen, halogen or methyl;

[0013] The structural formula of the isocyanoacetate of the compound of formula 2 is In formula 2, R is Me or Et;

[0014] The structural formula of the 4-formylpyrrole derivative of the compound of formula 3 is In formula 3, R 1 is hydrogen, halogen or methyl; R is Me or Et.

[0015] Preferably, the ratio of the volume of the organic solvent to the molar amount of the alkenyl nitrone compound of formula 1 is 6 mL:1 mmol.

[0016] Preferably, the base is cesium carbonate, and the molar ratio between the base and the alkenyl nitrone compound of formula 1 is 2:1;

[0017] Preferably, the metal silver salt is silver oxide.

[0018] Preferably, the organic solvent is 1,4-dioxane.

[0019] Preferably, the developing solvent used for the TLC tracking reaction is 3:1 petroleum ether / ethyl acetate.

[0020] Furthermore, the method for post-treatment of the reaction solution is: after the reaction is completed, the reaction is quenched with water, extracted with ethyl acetate, and then the organic phase is backwashed with water, dried over anhydrous sodium sulfate, distilled under reduced pressure, and then separated by silica gel column chromatography, and the obtained eluate is distilled under reduced pressure and dried to obtain a 4-formylpyrrole derivative of the compound of formula 3.

[0021] Preferably, the eluent used in the silica gel column chromatography is petroleum ether / ethyl acetate in a volume ratio of 4:1.

[0022] To achieve the above object, the present invention also adopts a technical solution: the use of the 4-formyl pyrrole derivative synthesized by the above silver-catalyzed method for synthesizing 4-formyl pyrrole derivatives in converting into N-sulfonylated pyrrole compounds of formula 5, the specific steps are: the 4-formyl pyrrole derivative of formula 3 and the p-toluenesulfonyl chloride of the compound of formula 4 are added as reaction raw materials to an organic solvent, a base and a catalyst are added, the reaction is stirred at room temperature, and the reaction is tracked by TLC until the reaction is complete. After the reaction solution is treated, the N-sulfonylated pyrrole compound of formula 5 is obtained, and its structural formula is In formula 5, R 1 is hydrogen, halogen or methyl; R is Me or Et.

[0023] Preferably, the catalyst is TBAHS, the base is KOH, and the organic solvent is DCM; the method for post-treatment of the reaction solution is: after the reaction is completed, the reaction is quenched with water, extracted with DCM, the organic phases are combined, and then the organic phases are backwashed with water, dried over anhydrous sodium sulfate, filtered, and distilled under reduced pressure, and then subjected to silica gel column chromatography to obtain the N-sulfonylated pyrrole compound of formula 5.

[0024] Compared with the prior art, the present invention has the following beneficial effects:

[0025] The invention uses a metal silver salt as a catalyst, uses an alkenyl nitrone compound and an isocyanoacetic acid ester as raw materials, and synthesizes a 4-formyl pyrrole compound in a one-pot method through a cycloaddition reaction; the invention is simple to operate, the reagents are readily available, the reaction conditions are mild, the reaction system is green and environmentally friendly, the product is easy to separate and purify, the yield is high, and the invention is suitable for synthesizing various highly functionalized 4-formyl pyrrole compounds, and is particularly suitable for large-scale industrial production. Application research confirms that the 4-formyl pyrrole compound of the invention can be further converted into an N-sulfonylated pyrrole compound. BRIEF DESCRIPTION OF THE DRAWINGS

[0026] Figure 1 The 4-formylpyrrole 3a prepared in Example 1 1 H-NMR nuclear magnetic resonance spectrum;

[0027] Figure 2 The 4-formylpyrrole 3a prepared in Example 1 13 C-NMR nuclear magnetic resonance spectrum;

[0028] Figure 3 The 4-formylpyrrole 3b prepared in Example 2 1 H-NMR nuclear magnetic resonance spectrum;

[0029] Figure 4 The 4-formylpyrrole 3b prepared in Example 2 13C-NMR nuclear magnetic resonance spectrum;

[0030] Figure 5 The 4-formylpyrrole 3c prepared in Example 3 1 H-NMR nuclear magnetic resonance spectrum;

[0031] Figure 6 The 4-formylpyrrole 3c prepared in Example 3 13 C-NMR nuclear magnetic resonance spectrum;

[0032] Figure 7 The 4-formylpyrrole 3d prepared in Example 4 1 H-NMR nuclear magnetic resonance spectrum;

[0033] Figure 8 The 4-formylpyrrole 3d prepared in Example 4 13 C-NMR nuclear magnetic resonance spectrum;

[0034] Fig. 9 The 4-formylpyrrole 3e prepared in Example 5 1 H-NMR nuclear magnetic resonance spectrum;

[0035] Fig.10 The 4-formylpyrrole 3e prepared in Example 5 13 C-NMR nuclear magnetic resonance spectrum;

[0036] Fig.11 The 4-formylpyrrole 3f prepared in Example 6 is 1 H-NMR nuclear magnetic resonance spectrum;

[0037] Fig.12 The 4-formylpyrrole 3f prepared in Example 6 is 13 C-NMR nuclear magnetic resonance spectrum.

[0038] Fig.13 3g of 4-formylpyrrole prepared in Example 7 1 H-NMR nuclear magnetic resonance spectrum;

[0039] Fig.14 3g of 4-formylpyrrole prepared in Example 7 13 C-NMR nuclear magnetic resonance spectrum;

[0040] Fig.15 is the N-sulfonylated pyrrole compound 5 prepared in Example 8 1 H-NMR nuclear magnetic resonance spectrum;

[0041] Fig.16is the N-sulfonylated pyrrole compound 5 prepared in Example 8 13 C-NMR nuclear magnetic resonance spectrum. DETAILED DESCRIPTION

[0042] The present invention is further described in detail below in conjunction with embodiments.

[0043] In the following examples, unless otherwise specified, alkenyl nitrone compounds, isocyanoacetates, metal silver salts and other reagents can be purchased from the market or obtained according to known literature reports.

[0044] Example 1

[0045] Preparation of 4-Formylpyrrole Derivative 3a

[0046]

[0047] To a 10 mL reaction tube equipped with a magnetic stirrer, (1Z, 2E)-N,3-diphenylprop-2-ene-1-imine oxide 1a (0.112 g, 0.5 mmol), silver oxide (0.023 g, 0.1 mmol), and cesium carbonate (0.325 g, 1 mmol) were added, and argon protection was added. Finally, 1,4-dioxane (3 mL) and ethyl isocyanoacetate 2a (54 μL, 0.5 mmol) were added. After stirring evenly, the mixture was placed in an 80 °C oil bath and continued to stir. TLC (developing solvent: V 石油醚 :V 乙酸乙酯 =3:1) detection substrate disappears, the reaction is over; the reaction solution is poured into water (30mL), extracted with ethyl acetate (3×10mL), the organic phases are combined, and then the organic phases are backwashed with water (3×10mL), and a viscous solid is obtained after drying with anhydrous sodium sulfate, filtering, and vacuum distillation. Finally, silica gel column chromatography (eluent is V 石油醚 :V 乙酸乙酯 =4:1) to obtain a white solid, which was confirmed to be 4-formylpyrrole compound 3a by NMR and MS, with a yield of 84%.

[0048] Hydrogen and carbon spectra Figure 1 and Figure 2 As shown, the spectrum analysis data is as follows 3a:

[0049] White solid; 1 H NMR (CDCl3, 400MHz):δ H 9.80(brs,1H,NH),9.66(s,1H),7.65(d,J=3.2Hz,1H),7.48–7.36(m,5H),4.21(q,J=7.2Hz,2H),1.15(t,J=14Hz,3H).( Figure 1 ); 13CNMR (CDCl3, 101MHz): δ C 13C NMR (101MHz, CHLOROFORM-D) δ187.1,160.7,133.1,131.5,130.7,127.9,127.7,125.8,125.3,120.6,60.8,13.9.( Figure 2 ); HRMS(ESI-TOF,m / z):calcdfor C 14 H 13 NO3[M+H] + ,244.0968;found,244.0977.

[0050] Example 2

[0051] 1a in Example 1 was replaced by 1b, and other conditions were the same as those in Example 1. The yield was 67%.

[0052]

[0053] Hydrogen and carbon spectra Figure 3 and Figure 4 As shown, the spectrum analysis data is as follows 3b:

[0054] White solid; 1 H NMR (CDCl3, 400MHz):δ H 9.70(brs,1H,NH),9.66(s,1H),7.64(d,J=3.2Hz,1H),7.41–7.36(m,4H),4.22(q,J=7.2Hz,2H),1.19(t,J=14Hz,3H).( Figure 3 ); 13 C NMR (CDCl3, 101MHz):δ C 13C NMR (101MHz, CHLOROFORM-D) δ186.5,160.6,134.0,132.0,131.4,130.1,127.9,126.1,125.7,120.8,62.5,14.0.( Figure 4 ); HRMS(ESI-TOF,m / z):calcd forC 14 H 12 ClNO3[M+H] + ,278.0578;found,278.0582.

[0055] Example 3

[0056] 1c was used to replace 1a in Example 1. Other conditions were the same as those in Example 1. The yield was 69%.

[0057]

[0058] Hydrogen and carbon spectra Figure 5 and Figure 6 As shown, the spectrum analysis data is as follows 3c:

[0059] White solid; 1 H NMR (CDCl3, 400MHz):δ H 9.97(brs,1H,NH),9.57(s,1H),7.66(d,J=3.2Hz,1H),7.48(d,J=7.6Hz,1H),7.37–7.32(m,3H),4.22–4.01(m,2H),1.07(t,J=14.4Hz,3H).( Figure 5 ); 13 C NMR (CDCl3, 101MHz):δ C 13C NMR (101MHz, CHLOROFORM-D) δ186.2,160.6,134.1,132.1,131.5,129.3,129.2,128.9,126.1,125.7,125.7,121.8,60.9,14.4.( Figure 6 ); HRMS(ESI-TOF,m / z):calcd for C 14 H 12 ClNO3[M+H] + ,278.0578;found,278.0585.

[0060] Example 4

[0061] 1d was used to replace 1a in Example 1. Other conditions were the same as those in Example 1. The yield was 85%.

[0062]

[0063] Hydrogen and carbon spectra Figure 7 and Figure 8 As shown, the spectrum analysis data is as follows 3d:

[0064] White solid; 11 H NMR (CDCl3, 400MHz):δ H9.70(brs,1H,NH),9.56(s,1H),7.67(s,1H),7.65(s,1H),7.38–7.28(m,2H),7.28(s,1H),4.22–4.01(m,2H),1.06(t,J=14.4Hz,3H).( Figure 7 ); 13 C NMR (CDCl3, 101MHz):δ C 13C NMR (101MHz, CHLOROFORM-D) δ186.2,160.7,133.8,133.7,132.4,131.9,129.5,126.7,125.7,125.4,124.4,60.9,13.7.( Figure 8 ); HRMS(ESI-TOF,m / z):calcd for C 14 H 12 BrNO3[M+H] + ,322.0073;found,322.0081.

[0065] Example 5

[0066] 1e was used to replace 1a in Example 1, and other conditions were the same as those in Example 1. The yield was 76%.

[0067]

[0068] Hydrogen and carbon spectra Fig. 9 and Fig.10 As shown, the spectrum analysis data is as follows 3e:

[0069] White solid; 1 H NMR (CDCl3, 400MHz):δ H 9.67(s,1H),9.64(brs,1H,NH),7.63(d,J=3.2Hz,1H),7.32(d,J=8.0Hz,2H),7. 22(d,J=7.6Hz,2H),4.22(q,J=6.8Hz,2H),2.41(s,3H),1.19(t,J=14.4Hz,3H).( Fig. 9 ); 13 C NMR (CDCl3, 101MHz):δ C 13C NMR (101MHz, CHLOROFORM-D) δ187.2,160.6,137.8,133.3,130.6,128.4,125.9,125.1,60.8,21.3,14.0.( Fig.10); HRMS(ESI-TOF,m / z):calcd for C 15 H 15 NO3[M+H] + ,258.1125;found,258.1136.

[0070] Example 6

[0071] 1f was used to replace 1a in Example 1. Other conditions were the same as those in Example 1. The yield was 67%.

[0072]

[0073] Hydrogen and carbon spectra Fig.11 and Fig.12 As shown, the spectrum analysis data is as follows 3f:

[0074] White solid; 1 H NMR (CDCl3, 400MHz):δ H 10.01(brs,1H,NH),9.48(s,1H),7.66(s,1H),7.31–7.27(m,2H),7.23-7.18(m,2H),4.19–4.01(m,2H),2.14(s,3H),1.04(t,J=14.8Hz,3H).( Fig.11 ); 13 C NMR (CDCl3, 101MHz)δ C (101MHz,CHLOROFORM-D)δ160.7,147.6,137.3,132.6,130.6,130.4,129.7, 129.4,129.0,128.0,126.4,125.3,121.3,120.4,117.0,60.4,20.1,13.8.( Fig.12 ); HRMS(ESI-TOF,m / z):calcd for C 15 H 15 NO3[M+H] + ,258.1125;found,258.1129.

[0075] Example 7

[0076] 2a in Example 1 was replaced by 2b, and other conditions were the same as in Example 1, and the yield was 66%.

[0077]

[0078] Hydrogen and carbon spectra Fig.13 and Fig.14As shown, the spectrum analysis data is as follows 3g:

[0079] White solid; 1 H NMR (CDCl3, 400MHz)δ H 9.66(s,1H),9.58(brs,1H,NH),7.66(s,1H),7.44-7.41(m,5H),3.74(s,3H).( Fig.13 ); 13 C NMR (CDCl3, 101MHz)δ C 13C NMR(101MHz,CHLOROFORM-D)δ13C NMR(101MHz,CHLOROFORM-D)δ187.0,133.2,130.6,128.0,127.8,125.9,125.2,120.3,51.7.( Fig.14 ); HRMS(ESI-TOF,m / z):calcd for C 13 H 11 NO3[M+H] + ,230.0812;found,230.0815.

[0080] Example 8

[0081] The 4-formylpyrrole derivative of the present invention can be further converted into an N-sulfonylated pyrrole compound 5. The compound has a wide range of uses and can be used as an intermediate product of various special chemical derivatives. It is an important raw material for producing various pyrrole compounds. At the same time, tertiary amine compounds are an important class of organic synthesis intermediates and play an important role in the synthesis of natural products and organic drugs. The 4-formylpyrrole derivative synthesized by the present invention can be further converted into an N-sulfonylated pyrrole compound, providing a new method for synthesizing N-sulfonylated pyrrole compounds. The reaction synthesis route is as follows:

[0082]

[0083] 4-Formylpyrrole compound 3a (24 mg, 0.1 mmol), p-toluenesulfonyl chloride 4 (23 mg, 0.12 mmol), KOH (11 mg, 0.2 mmol), TBAHS (2 mg, 5% mmol) were added to a 10 mL reaction tube equipped with a magnetic stirrer, and finally DCM (2 mL) was added, stirred evenly, and reacted at room temperature. TLC (developing solvent: V 石油醚 :V 乙酸乙酯=10:1) detection substrate disappears, the reaction is over. The reaction solution was poured into water (30 mL), extracted with DCM (3×10 mL), the organic phases were combined, and then backwashed with water (3×10 mL). After drying with anhydrous sodium sulfate, filtration, and vacuum distillation, a viscous solid was obtained. Finally, silica gel column chromatography (eluent: V 石油醚 :V 乙酸乙酯 =15:1) to give a white solid 5 in a yield of 88%.

[0084] Hydrogen and carbon spectra Fig.15 and Fig.16 As shown, the spectrum analysis data is as follows:

[0085] 1 H NMR (CDCl3, 400MHz)δ H 9.67(s,1H),8.20(s,1H),7.99(d,J=6.4Hz,2H),7.42-7.36(m,5H),7.30- 7.28(m,2H),4.07(q,J=7.2Hz,2H),2.47(s,3H),0.093(t,J=7.2Hz,3H).( Fig.15 ); 13 C NMR(CDCl3,101MHz)δ13C NMR(101MHz,CHLOROFORM-D)δ186.0,160.0,146.2,134.6,133.6,130.7,129.9,129.8,129.5,128.8,128.2,127.9,124.6,123.9,61.5,21.8,13.4.( Fig.16 ).

Claims

1. A method for synthesizing 4-formylpyrrole derivatives using silver catalysis, characterized in that: The specific steps are: add the alkenyl nitrone compound of formula 1 and the isocyanoacetate of formula 2 as reaction raw materials into an organic solvent, add a base under the catalysis of a metal silver salt, add argon protection, stir and react at 80° C., track the reaction by TLC until the reaction is complete, and after treating the reaction solution, obtain the 4-formylpyrrole derivative of formula 3; Wherein, the molar ratio between the alkenyl nitrone compound and the isocyanoacetate is 1:1; The molar ratio between the metal silver salt and the alkenyl nitrone compound is 1:5; The organic solvent is one of 1,4-dioxane, N,N-dimethylformamide and dimethyl sulfoxide; The base is cesium carbonate; The metallic silver salt is silver oxide; The structural formula of the alkenyl nitrone compound of Formula 1 is , in formula 1, R 1 is hydrogen, halogen or methyl; The structural formula of the isocyanoacetate of the compound of formula 2 is , in Formula 2, R is selected from Me or Et; The structural formula of the 4-formylpyrrole derivative of the compound of formula 3 is , in formula 3, R 1 is hydrogen, halogen or methyl; R is Me or Et.

2. The method for synthesizing 4-formylpyrrole derivatives by silver catalysis according to claim 1, characterized in that: The ratio of the volume of the organic solvent to the molar amount of the alkenyl nitrone compound of Formula 1 is 6 mL:1 mmol.

3. A method for synthesizing 4-formylpyrrole derivatives by silver catalysis according to claim 1 or 2, characterized in that: The molar ratio between the base and the alkenyl nitrone compound of formula 1 is 2:

1.

4. A method for synthesizing 4-formylpyrrole derivatives by silver catalysis according to claim 1 or 2, characterized in that: The organic solvent is 1,4-dioxane.

5. A method for synthesizing 4-formylpyrrole derivatives by silver catalysis according to claim 1 or 2, characterized in that: The developing solvent used for the TLC tracking reaction was 3:1 petroleum ether / ethyl acetate.

6. A method for synthesizing 4-formylpyrrole derivatives by silver catalysis according to claim 1 or 2, characterized in that: The post-treatment method of the reaction solution is: after the reaction is completed, the reaction is quenched with water, extracted with ethyl acetate, and then the organic phase is backwashed with water, dried over anhydrous sodium sulfate, distilled under reduced pressure, and then separated by silica gel column chromatography, and the obtained eluent is distilled under reduced pressure and dried to obtain the 4-formylpyrrole derivative of the compound of formula 3.

7. The method for synthesizing 4-formylpyrrole derivatives by silver catalysis according to claim 6, characterized in that: The eluent used in the silica gel column chromatography is petroleum ether / ethyl acetate in a volume ratio of 4:1.

Images