A method for synthesizing a pyrrole compound

Abstract

The application discloses a method for synthesizing a pyrrole compound. The method comprises the following steps: mixing a beta-nitrostyrene compound, an alpha-fluoro-beta-keto ester compound, cesium carbonate and ethanol, and then performing an addition reaction at 40-60 DEG C; cooling to room temperature after the reaction is completed; then adding acetic acid and zinc particles; and performing a ring formation reaction at 60-100 DEG C to obtain the pyrrole compound. The method does not need to add a noble metal catalyst and a large amount of an oxidation-reduction agent, the reaction is performed under normal pressure, the operation is simple and convenient, raw materials are cheap and easy to obtain, and the method is suitable for large-scale production.

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis and relates to a method for synthesizing pyrrole compounds. Background Technology

[0002] Pyrrole is a very important five-membered aromatic heterocycle, a key structure in many natural products, synthetic drugs, and novel materials. Traditional methods for preparing pyrrole compounds involve the condensation reaction of carbonyl compounds with amines, such as the Knorr pyrrole synthesis, Hantzsch pyrrole synthesis, Barton–Zard pyrrole synthesis, and Paal-Knorr reaction. However, these reactions often require harsh conditions such as high temperatures, strong acids, and strong bases, resulting in poor functional group tolerance. Furthermore, selectivity issues are frequently encountered in the synthesis of polysubstituted pyrrole rings, limiting their application. In recent years, transition metal-catalyzed cyclization and multi-component coupling have been developed for the synthesis of polysubstituted pyrroles. Some specific existing methods for synthesizing pyrrole compounds are described below.

[0003] Reference 1 (Wang HY, Mueller DS, Sachwani RM, et al. Regioselective synthesis of 2,3,4- or 2,3,5-trisubstituted pyrroles via [3,3] or [1,3] rearrangements of O-vinyl oximes[J]. The Journal of Organic Chemistry, 2011, 76(9): 3203-3221.) uses an iridium catalyst to isomerize O-allyl oxime to O-vinyl oxime, and further converts O-vinyl oxime to 2,3,4- or 2,3,5-trisubstituted pyrroles. The regioselectivity of pyrrole formation can be controlled by different bases such as DBU and other reaction conditions. The disadvantages of this method are that it requires noble metal catalysts such as iridium and silver, and the reaction precursors require multi-step synthesis, limiting the substrate range. The reaction formula is as follows:

[0004]

[0005] Reference 2 (Li L, Zhao MN, Ren ZH, et al. Synthesis of tetrasubstituted NHpyrroles and polysubstituted furans via an addition and cyclization strategy[J]. Synthesis, 2012, 44(04): 532-540.) uses ferric chloride to catalyze the cyclization of β-nitrostyrene and enamino esters to construct polysubstituted pyrroles. The method is relatively simple, but it requires a metal catalyst and has a very limited substrate range. The yield of some structures is very low (below 40%). The reaction formula is as follows:

[0006]

[0007] Reference 3 (Umeda R, Mashino T, Nishiyama Y. Synthesis of multisubstituted 1H-pyrrole: Selenium-catalyzed reaction of γ-nitro substituted carbonyl compounds and carbon monoxide[J]. Tetrahedron, 2014, 70(29): 4395-4399.) uses elemental selenium as a catalyst and carbon monoxide as a reducing agent to convert γ-nitro substituted carbonyl compounds into multisubstituted pyrrole compounds. However, this method uses gas as a raw material, the reaction is carried out at high temperature, and the reaction precursors require multiple steps to prepare, which limits its application. The reaction formula is as follows:

[0008]

[0009] Reference 4 (Wu W, Wen S, Zhang X, et al. Silver-Catalyzed Regioselective Synthesis of Highly Substituted 2-Trifluoromethyl Pyrroles[J]. Organic Letters, 2021, 23(16): 6352-6356.) uses ethylene azide and ethyl 4,4,4-trifluoro-3-oxobutyrate to selectively synthesize multi-substituted 2-trifluoromethyl pyrrole derivatives via silver catalysis. The reaction yield is high and can be scaled up to gram scale. However, this method also uses silver catalysts and has certain limitations in substrate selection. The reaction formula is as follows:

[0010]

[0011] The aforementioned synthetic routes for pyrrole all have certain drawbacks, such as the need for expensive metal catalysts and other additives, which leads to problems in post-processing, and the need for multi-step pre-synthesis of the reaction substrate with limited scope. Therefore, there is an urgent need to develop a pyrrole synthesis method that does not require expensive and complex metal catalysts and additives and has simple reaction conditions. Summary of the Invention

[0012] The purpose of this invention is to provide a method for synthesizing pyrrole compounds. This method uses β-nitrostyrene compounds and α-fluoro-β-keto ester compounds as raw materials. No additional catalyst is required during the reaction, the reaction conditions are simple and mild, the raw materials are readily available, and the entire reaction is simple and easy to perform.

[0013] The technical solution for achieving the objective of this invention is as follows:

[0014] A method for synthesizing pyrrole compounds, the principle of which is as follows:

[0015]

[0016] Where R 1 It is hydrogen, methyl, or fluorine group, R 2 For hydrogen, methyl, R 3 Methyl, trifluoromethyl, R 4 It is ethyl or benzyl.

[0017] The specific steps are as follows:

[0018] β-nitrostyrene compound (B), α-fluoro-β-keto ester compound (C), cesium carbonate, and ethanol were mixed and subjected to an addition reaction in an oil bath at 40–60 °C. After the reaction was completed, the mixture was cooled to room temperature. Acetic acid and zinc granules were then added sequentially, and a cyclization reaction was carried out in an oil bath at 60–100 °C. After the reaction was completed, the mixture was cooled to room temperature, and the reaction solution was extracted. The obtained organic phase was removed by vacuum distillation to remove the solvent, and then column chromatography was performed using an eluent to separate pyrrole compound (A).

[0019] Further, the β-nitrostyrene compounds are β-nitrostyrene, p-fluoroβ-nitrostyrene, p-methylβ-nitrostyrene, or (E)-(2-nitroprop-1-en-1-yl)benzene; the α-fluoro-β-keto ester compounds are ethyl 2-fluoroacetoacetate, ethyl 2,4,4,4-tetrafluoro-3-oxobutyrate, or benzyl 2-fluoro-3-oxobutyrate; the pyrrole compounds are ethyl 2-methyl-4-phenyl-1H-pyrrole-3-carboxylate, ethyl 4-(4-fluorophenyl)-2-(trifluoromethyl)-1H-pyrrole-3-carboxylate, benzyl 4-(4-fluorophenyl)-2-methyl-1H-pyrrole-3-carboxylate, ethyl 4-(p-tolyl)-2-(trifluoromethyl)-1H-pyrrole-3-carboxylate, or ethyl 2,5-dimethyl-4-phenyl-1H-pyrrole-3-carboxylate.

[0020] Furthermore, the molar ratio of β-nitrostyrene compounds and α-fluoro-β-keto ester compounds is 1:1.5-1:2, preferably 1:1.5.

[0021] Furthermore, the molar ratio of β-nitrostyrene compounds to cesium carbonate is 1:1.5-1:2, preferably 1:1.5.

[0022] Furthermore, the addition reaction time is 2-4 hours, preferably 3 hours.

[0023] Furthermore, the cyclization reaction time is 6-12 hours, preferably 9 hours.

[0024] Furthermore, the extraction solvent is a mixture of ethyl acetate and water in a volume ratio of 1:1.

[0025] Furthermore, the eluent is a mixture of ethyl acetate and petroleum ether in a volume ratio of 3:7.

[0026] The significant advantages of this invention compared to existing technologies are:

[0027] (1) The reaction conditions of this invention are simple and mild, requiring no expensive and complex catalysts. The reaction is carried out under normal pressure and is easy to operate.

[0028] (2) The reaction steps of the present invention are simple and the conversion rate is high, which can easily obtain high-purity products and is suitable for large-scale industrial production.

[0029] (3) The raw materials used in this invention, such as β-nitrostyrene compounds and α-fluoro-β-keto esters, are readily available, inexpensive, stable, and easy to use. Attached Figure Description

[0030] Figure 1 It is ethyl 2-methyl-4-phenyl-1H-pyrrole-3-carboxylic acid. 1 H NMR spectrum;

[0031] Figure 2 It is ethyl 2-methyl-4-phenyl-1H-pyrrole-3-carboxylic acid. 13 C NMR spectrum;

[0032] Figure 3 It is ethyl 4-(4-fluorophenyl)-2-(trifluoromethyl)-1H-pyrrole-3-carboxylic acid. 1 H NMR spectrum;

[0033] Figure 4 It is ethyl 4-(4-fluorophenyl)-2-(trifluoromethyl)-1H-pyrrole-3-carboxylic acid. 19 F NMR spectrum;

[0034] Figure 5 It is benzyl 4-(4-fluorophenyl)-2-methyl-1H-pyrrole-3-carboxylic acid ester. 1 H NMR spectrum;

[0035] Figure 6 It is benzyl 4-(4-fluorophenyl)-2-methyl-1H-pyrrole-3-carboxylic acid ester. 19 F NMR spectrum;

[0036] Figure 7 It is ethyl 4-(p-tolyl)-2-(trifluoromethyl)-1H-pyrrole-3-carboxylic acid. 1 H NMR spectrum;

[0037] Figure 8 It is ethyl 4-(p-tolyl)-2-(trifluoromethyl)-1H-pyrrole-3-carboxylic acid. 19 F NMR spectrum;

[0038] Figure 9 It is ethyl 2,5-dimethyl-4-phenyl-1H-pyrrole-3-carboxylate. 1 H NMR spectrum;

[0039] Figure 10 It is ethyl 2,5-dimethyl-4-phenyl-1H-pyrrole-3-carboxylate. 13 C NMR spectrum. Detailed Implementation

[0040] To better understand the present invention, the technical solution of the present invention will be further described in detail below through specific embodiments and accompanying drawings.

[0041] Example 1

[0042] In a reaction tube, 74.5 mg (0.5 mmol) of β-nitrostyrene, 111 mg (0.75 mmol) of ethyl 2-fluoroacetoacetate, 244 mg (0.75 mmol) of cesium carbonate, and 3 mL of ethanol were added sequentially. The reaction was then heated to 40 °C with stirring in an oil bath for 3 hours. After the reaction was completed, the mixture was cooled to room temperature. 3 mL of acetic acid and 162 mg (2.5 mmol) of zinc granules were added sequentially, and the reaction was again heated to 90 °C with stirring in an oil bath for 9 hours. After the reaction was completed, the mixture was cooled to room temperature and extracted three times with ethyl acetate and water. The combined organic phases were then distilled under reduced pressure to remove the solvent. The crude product was separated by column chromatography (eluent: a mixture of ethyl acetate and petroleum ether in a 3:7 volume ratio) to obtain 77.8 mg of ethyl 2-methyl-4-phenyl-1H-pyrrole-3-carboxylic acid, in 68% yield.

[0043] ethyl 2-methyl-4-phenyl-1H-pyrrole-3-carboxylic acid 1 See H NMR spectrum Figure 1 , 13 See the C NMR spectrum. Figure 2 .

[0044] 1 H NMR(500MHz,Chloroform-d)δ9.08(s,1H),7.29(d,J=4.3Hz,4H),7.24(p,J=4.2 Hz,1H),6.57(s,1H),4.10(q,J=7.1Hz,2H),2.34(s,3H),1.13(t,J=7.1Hz,3H).

[0045] 13 C NMR (126MHz, Chloroform-d) δ165.93,134.21,132.34,128.24,126.56,125.29,121.27,115.24,103.99,58.91,12.96,8.95.

[0046] Example 2

[0047] 83.5 mg (0.5 mmol) of p-fluoroβ-nitrostyrene, 151 mg (0.75 mmol) of ethyl 2,4,4,4-tetrafluoro-3-oxobutyrate, 244 mg (0.75 mmol) of cesium carbonate, and 3 mL of ethanol were added to a reaction tube. The reaction was then heated to 40 °C with stirring in an oil bath for 3 hours. After the reaction was completed, the mixture was cooled to room temperature. 3 mL of acetic acid and 162 mg (2.5 mmol) of zinc granules were added sequentially to the reaction tube. The reaction was then heated to 90 °C with stirring in an oil bath for 9 hours. After the reaction was completed, the mixture was cooled to room temperature and extracted three times with ethyl acetate and water. The combined organic phases were then distilled under reduced pressure to remove the solvent. The crude product was separated by column chromatography (eluent: a mixture of ethyl acetate and petroleum ether in a 3:7 volume ratio) to obtain 91.5 mg of ethyl 4-(4-fluorophenyl)-2-(trifluoromethyl)-1H-pyrrole-3-carboxylic acid, in 61% yield.

[0048] ethyl 4-(4-fluorophenyl)-2-(trifluoromethyl)-1H-pyrrole-3-carboxylic acid 1 See H NMR spectrum Figure 3 , 19 See F NMR image Figure 4 .

[0049] 1 H NMR(500MHz,Chloroform-d)δ9.22(s,1H),7.32(dd,J=8.5,5.5Hz,2H),7.02(t,J =8.7Hz,2H),6.75(d,J=2.5Hz,1H),4.21(q,J=7.1Hz,2H),1.20(t,J=7.1Hz,3H).

[0050] 19 F NMR(470MHz,Chloroform-d)δ-57.84(s,3F),-114.37(s,1F).

[0051] Example 3

[0052] 83.5 mg (0.5 mmol) of p-fluoroβ-nitrostyrene, 144 mg (0.75 mmol) of benzyl 2-fluoro-3-oxobutyrate, 244 mg (0.75 mmol) of cesium carbonate, and 3 mL of ethanol were added to a reaction tube. The reaction was then heated to 40 °C with stirring in an oil bath for 3 hours. After the reaction was completed, the mixture was cooled to room temperature. 3 mL of acetic acid and 162 mg (2.5 mmol) of zinc granules were added sequentially to the reaction tube. The reaction was then heated to 90 °C with stirring in an oil bath for 9 hours. After the reaction was completed, the mixture was cooled to room temperature and extracted three times with ethyl acetate and water. The combined organic phases were then distilled under reduced pressure to remove the solvent. The crude product was separated by column chromatography (eluent: a mixture of ethyl acetate and petroleum ether in a 3:7 volume ratio) to give 88.1 mg of 4-(4-fluorophenyl)-2-methyl-1H-pyrrole-3-carboxylic acid benzyl ester, in 57% yield.

[0053] 4-(4-fluorophenyl)-2-methyl-1H-pyrrole-3-carboxylic acid benzyl ester 1 See H NMR spectrum Figure 5 , 19 See F NMR image Figure 6 .

[0054] 1 H NMR(500MHz,Chloroform-d)δ8.63-8.37(m,1H),7.37(d,J=4.4Hz,2H),7.29(t,J=2.9Hz,3H) ,7.16(dd,J=7.0,2.8Hz,2H),6.96-6.92(m,2H),6.54-6.47(m,1H),5.17(s,2H),2.52(s,3H).

[0055] 19 F NMR(470MHz,Chloroform-d)δ-116.03.

[0056] Example 4

[0057] 81.5 mg (0.5 mmol) of p-methylβ-nitrostyrene, 151 mg (0.75 mmol) of ethyl 2,4,4,4-tetrafluoro-3-oxobutyrate, 244 mg (0.75 mmol) of cesium carbonate, and 3 mL of ethanol were added to a reaction tube. The reaction was then heated to 40 °C with stirring in an oil bath for 3 hours. After the reaction was completed, the mixture was cooled to room temperature. 3 mL of acetic acid and 162 mg (2.5 mmol) of zinc granules were added sequentially to the reaction tube. The reaction was then heated to 90 °C with stirring in an oil bath for 9 hours. After the reaction was completed, the mixture was cooled to room temperature and extracted three times with ethyl acetate and water. The combined organic phases were then distilled under reduced pressure to remove the solvent. The crude product was separated by column chromatography (eluent: a 3:7 mixture of ethyl acetate and petroleum ether) to obtain 93.5 mg of ethyl 4-(p-tolyl)-2-(trifluoromethyl)-1H-pyrrole-3-carboxylic acid, in 63% yield.

[0058] 4-(p-Tolyl)-2-(trifluoromethyl)-1H-pyrrole-3-carboxylic acid ethyl ester 1 See H NMR spectrum Figure 7 , 19 See F NMR image Figure 8 .

[0059] 1 H NMR(500MHz,Chloroform-d)δ9.06(s,1H),7.30-7.25(m,2H),7.16(d,J=7.8Hz,2H ), 6.78 (d, J = 2.7Hz, 1H), 4.24 (q, J = 7.1Hz, 2H), 2.36 (s, 3H), 1.23 (t, J = 7.1Hz, 3H).

[0060] 19 F NMR(470MHz,Chloroform-d)δ-57.73.

[0061] Example 5

[0062] 81.5 mg (0.5 mmol) of (E)-(2-nitroprop-1-en-1-yl)benzene, 111 mg (0.75 mmol) of ethyl 2-fluoroacetoacetate, 244 mg (0.75 mmol) of cesium carbonate, and 3 mL of ethanol were added to a reaction tube. The reaction was then heated to 40 °C with stirring in an oil bath for 3 hours. After the reaction was completed, the mixture was cooled to room temperature. 3 mL of acetic acid and 162 mg (2.5 mmol) of zinc granules were added sequentially to the reaction tube. The reaction was then heated to 90 °C with stirring in an oil bath for 9 hours. After the reaction was completed, the mixture was cooled to room temperature and extracted three times with ethyl acetate and water. The combined organic phases were then distilled under reduced pressure to remove the solvent. The crude product was separated by column chromatography (eluent: a mixture of ethyl acetate and petroleum ether in a 3:7 volume ratio) to give 78.9 mg of ethyl 2,5-dimethyl-4-phenyl-1H-pyrrole-3-carboxylic acid, in 65% yield.

[0063] ethyl 2,5-dimethyl-4-phenyl-1H-pyrrole-3-carboxylate 1 See H NMR spectrum Figure 9 , 13 See the C NMR spectrum. Figure 10 .

[0064] 1 H NMR(500MHz,Chloroform-d)δ8.76(s,1H),7.30(t,J=7.4Hz,2H),7.25-7.19(m,1H),7.17 (d,J=7.5Hz,2H),4.01(q,J=7.1Hz,2H),2.32(s,3H),2.07(s,3H),1.02(t,J=7.1Hz,3H).

[0065] 13 C NMR (126MHz, Chloroform-d) δ166.24,134.86,131.00,129.36,126.39,124.94,122.60,116.98,103.52,58.62,12.82,8.85,7.78.

[0066] Comparative Example 1

[0067] This comparative example uses sodium carbonate as a catalyst, specifically:

[0068] In a reaction tube, 74.5 mg (0.5 mmol) of β-nitrostyrene, 111 mg (0.75 mmol) of ethyl 2-fluoroacetoacetate, 79.5 mg (0.75 mmol) of sodium carbonate, and 3 mL of ethanol were added sequentially. The reaction was then heated to 40 °C with stirring in an oil bath for 3 hours. After the reaction was completed, the mixture was cooled to room temperature. 3 mL of acetic acid and 162 mg (2.5 mmol) of zinc granules were added sequentially, and the reaction was again heated to 90 °C with stirring in an oil bath for 9 hours. After the reaction was completed, the mixture was cooled to room temperature and extracted three times with ethyl acetate and water. The combined organic phases were then distilled under reduced pressure to remove the solvent. The crude product was separated by column chromatography (eluent: a mixture of ethyl acetate and petroleum ether in a 3:7 volume ratio) to obtain 26.3 mg of ethyl 2-methyl-4-phenyl-1H-pyrrole-3-carboxylic acid, in 23% yield.

[0069] Comparative Example 2

[0070] This comparative example uses cesium carbonate as a catalyst, specifically:

[0071] In a reaction tube, 74.5 mg (0.5 mmol) of β-nitrostyrene, 111 mg (0.75 mmol) of ethyl 2-fluoroacetoacetate, 244 mg (0.75 mmol) of cesium carbonate, and 3 mL of methanol were added sequentially. The reaction was then heated to 40 °C with stirring in an oil bath for 3 hours. After the reaction was completed, the mixture was cooled to room temperature. 3 mL of acetic acid and 162 mg (2.5 mmol) of zinc granules were added sequentially, and the reaction was again heated to 90 °C with stirring in an oil bath for 9 hours. After the reaction was completed, the mixture was cooled to room temperature and extracted three times with ethyl acetate and water. The combined organic phases were then distilled under reduced pressure to remove the solvent. The crude product was separated by column chromatography (eluent: a mixture of ethyl acetate and petroleum ether in a 3:7 volume ratio) to obtain 46.9 mg of ethyl 2-methyl-4-phenyl-1H-pyrrole-3-carboxylic acid, in 41% yield.

[0072] Comparative Example 3

[0073] In this comparative example, acetonitrile was used as the reaction solvent, specifically:

[0074] 74.5 mg (0.5 mmol) of β-nitrostyrene, 111 mg (0.75 mmol) of ethyl 2-fluoroacetoacetate, 244 mg (0.75 mmol) of cesium carbonate, and 3 mL of acetonitrile were added sequentially to a reaction tube. The reaction was then heated to 40 °C with stirring in an oil bath for 3 hours. After the reaction was completed, the mixture was cooled to room temperature. 3 mL of acetic acid and 162 mg (2.5 mmol) of zinc granules were added sequentially to the reaction tube. The reaction was then heated to 90 °C with stirring in an oil bath for 9 hours. After the reaction was completed, the mixture was cooled to room temperature and extracted three times with ethyl acetate and water. The combined organic phases were then distilled under reduced pressure to remove the solvent. Column chromatography (using a 3:7 mixture of ethyl acetate and petroleum ether as eluent) of the crude product did not yield the corresponding ethyl 2-methyl-4-phenyl-1H-pyrrole-3-carboxylic acid product.

Claims

1. A method for synthesizing pyrrole compounds, characterized in that, The specific steps are as follows: A mixture of β-nitrostyrene compounds, α-fluoro-β-keto esters, cesium carbonate, and ethanol was subjected to an addition reaction in an oil bath at 40–60 °C. After the reaction was completed, the mixture was cooled to room temperature. Subsequently, acetic acid and zinc granules were added sequentially, and a cyclization reaction was carried out in an oil bath at 60–100 °C. After the reaction was completed, the mixture was cooled to room temperature, and the reaction solution was extracted. The solvent was removed by vacuum distillation of the obtained organic phase, and then column chromatography was performed using an eluent to separate the pyrrole compounds. The synthetic route is as follows: ， Where R 1 It is hydrogen, methyl, or fluorine group, R 2 For hydrogen, methyl, R 3 Methyl, trifluoromethyl, R 4 It is ethyl or benzyl.

2. The method according to claim 1, characterized in that, β-Nitrostyrene compounds include β-nitrostyrene, p-fluoroβ-nitrostyrene, p-methylβ-nitrostyrene, or (E)-(2-nitroprop-1-en-1-yl)benzene; α-fluoro-β-keto ester compounds include ethyl 2-fluoroacetoacetate, ethyl 2,4,4,4-tetrafluoro-3-oxobutyrate, or benzyl 2-fluoro-3-oxobutyrate; pyrrole compounds include ethyl 2-methyl-4-phenyl-1H-pyrrole-3-carboxylate, ethyl 4-(4-fluorophenyl)-2-(trifluoromethyl)-1H-pyrrole-3-carboxylate, benzyl 4-(4-fluorophenyl)-2-methyl-1H-pyrrole-3-carboxylate, ethyl 4-(p-tolyl)-2-(trifluoromethyl)-1H-pyrrole-3-carboxylate, or ethyl 2,5-dimethyl-4-phenyl-1H-pyrrole-3-carboxylate.

3. The method according to claim 1, characterized in that, The molar ratio of β-nitrostyrene compounds to α-fluoro-β-keto esters is 1:1.5-1:

2.

4. The method according to claim 1, characterized in that, The molar ratio of β-nitrostyrene compounds to cesium carbonate is 1:1.5-1:

2.

5. The method according to claim 1, characterized in that, The addition reaction time is 2-4 h.

6. The method according to claim 1, characterized in that, The cyclization reaction takes 6-12 hours.

7. The method according to claim 1, characterized in that, The addition reaction time was 3 hours, and the cyclization reaction time was 9 hours.

8. The method according to claim 1, characterized in that, The extraction solvent was a mixture of ethyl acetate and water in a volume ratio of 1:

1.

9. The method according to claim 1, characterized in that, The eluent was a mixture of ethyl acetate and petroleum ether in a volume ratio of 3:7.

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