CN114181182B - Synthesis method of polysubstituted 4H-pyran compound - Google Patents
Synthesis method of polysubstituted 4H-pyran compound Download PDFInfo
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Abstract
The invention discloses a method for synthesizing a polysubstituted 4H-pyran compound, belonging to the field of organic synthesis. The method comprises the following steps: under the protection of nitrogen, sequentially adding beta, gamma-unsaturated-alpha-keto ester, alkyne, lewis acid and solvent into a reactor, stirring at a certain temperature until the reaction is completed, and separating by column chromatography to obtain the polysubstituted 4H-pyran compound. The synthesis method has the advantages of high yield, wide substrate application range, simple operation, mild reaction conditions, convenient post-treatment and the like. The reaction equation is as follows:
Description
Technical Field
The invention discloses a synthesis method of a polysubstituted 4H-pyran compound, which belongs to the technical field of organic synthesis.
Background
Polysubstituted 4H-pyrans are an important class of organic heterocyclic molecules, widely existing in natural products, with good biological and pharmacological activity (bioorg. Med. Chem.,2004,12,2199-2218); other types of heterocyclic compounds and functional molecules can also be constructed as synthons, such as Dyes (j. Org. Chem.,2021,86,3213-3222), organic luminescent materials (Dyes Pigments,2021,193,109537), and the like. The [4+2] cycloaddition reaction of α, β -unsaturated carbonyl compounds with alkynes is one of the common methods for synthesizing such compounds. The currently reported methods all need preactivated alpha, beta-unsaturated carbonyl compounds, and the substrate range is limited; noble metal catalysis is required in the reaction, and the reaction conditions are more severe (J.Am.chem.Soc.; 2009,131,1350-1351; J.Am.chem.Soc.; 2015,137,12478-12481; org.Lett.; 2018,20,1074-1077). Therefore, the development of a novel synthesis method of the polysubstituted 4H-pyran compound with mild conditions and wide substrate applicability has great significance.
Disclosure of Invention
The invention aims to solve the problems of limited substrate, harsh reaction conditions and the like in the existing synthesis process of the polysubstituted 4H-pyran compound, and provides a novel synthesis method of the polysubstituted 4H-pyran compound, which has mild conditions and wide substrate applicability.
In order to achieve the above object, the present invention provides a synthesis method of a polysubstituted 4H-pyran compound, wherein the chiral polysubstituted 4H-pyran compound has a structure shown in formula I:
wherein R is 1 Any one of saturated alkyl, substituted alkyl, aryl, substituted aryl, naphthyl and thienyl.
R 2 Selected from any one of methyl, ethyl and isopropyl.
R 3 、R 4 Any two of saturated alkyl, substituted alkyl, aryl, substituted aryl, naphthyl and thienyl which are the same or different.
The substituent of the substituted alkyl and the substituted aryl is any one of halogen atom, saturated alkyl, aryl, ester group, trifluoromethyl, nitro, hydroxyl and alkoxy.
The method comprises the following steps: under the protection of nitrogen, sequentially adding beta, gamma-unsaturated-alpha-keto ester, alkyne, lewis acid and solvent into a reactor, stirring at a certain temperature until the reaction is completed, and separating by column chromatography to obtain the polysubstituted 4H-pyran compound, wherein the chemical process is shown in a reaction formula II:
the Lewis acid is selected from any different one of ferric bromide, hafnium chloride, indium bromide and indium triflate.
The solvent is selected from any one of dichloromethane, chloroform, 1, 2-dichloroethane, tetrahydrofuran, toluene and acetonitrile.
The molar ratio of the beta, gamma-unsaturated-alpha-keto ester, alkyne and Lewis acid is 1.0 (1.0-10.0): 0.05-0.3.
The reaction time is 0.5-6h.
The reaction temperature is 0-60 ℃.
After the reaction, column chromatography was performed using a mixed solvent of petroleum ether and ethyl acetate.
The beneficial effects of the invention are as follows: the synthesis method of the polysubstituted 4H-pyran compound provided by the invention is scientific and reasonable, and has the advantages of high yield, wide substrate application range, simplicity in operation, mild reaction conditions, convenience in post-treatment and the like.
Drawings
FIG. 1 is an NMR spectrum of compound (3 aa) prepared in example 1;
FIG. 2 is an NMR spectrum of the compound (3 ba) prepared in example 2;
FIG. 3 is an NMR chart of the compound (3 ca) prepared in example 3;
FIG. 4 is an NMR chart of the compound (3 db) prepared in example 4;
FIG. 5 is an NMR spectrum of compound (3 dc) prepared in example 5;
FIG. 6 is an NMR chart of the compound (3 dd) produced in example 6.
Detailed Description
The method of the present invention is described herein by way of specific examples, but the present invention is not limited thereto, and any modification, equivalent substitution, improvement, etc. within the scope of the technical idea of the present invention should be included in the scope of the present invention.
Example 1:
the reaction equation is as follows:
under the protection of nitrogen, the compounds 1a (5 mmol), 2a (20 mmol) and hafnium chloride (1.0 mmol) were added to the reactor, 50mL of methylene chloride was added, and the mixture was stirred at room temperature until the reaction was completed. After the reaction is completed, the crude product obtained by concentrating the reaction liquid by a rotary evaporator is separated by column chromatography by a mixed solvent of petroleum ether and ethyl acetate in a volume ratio of 50:1, and pure 3aa is obtained, and the yield is 75%.
The nuclear magnetic data of 3aa are as follows:
1 H NMR(500MHz,CDCl 3 )δ7.31(d,J＝6.3Hz,6H),7.24(dd,J＝5.9,3.7Hz,1H),7.19-7.12(m,3H),7.09-7.01(m,3H),6.86(d,J＝7.3Hz,2H),6.30(d,J＝5.4Hz,1H),5.15(dt,J＝12.4,6.2Hz,1H),4.31(d,J＝5.4Hz,1H),1.31(dd,J＝5.8,4.3Hz,6H)ppm.
13 C NMR(125MHz,CDCl 3 )δ161.37,147.16,144.16,140.75,139.03,134.37,129.73,129.35,128.88,128.49,128.27,128.08,127.75,127.21,126.85,114.14,113.41,69.10,45.02,21.85ppm.
example 2
The reaction equation is as follows:
under the protection of nitrogen, the compound 1b (5 mmol), 2a (20 mmol) and hafnium chloride (1.0 mmol) were added to the reactor, 50mL of 1, 2-dichloroethane was added, and the mixture was stirred at room temperature until the reaction was completed. After the reaction was completed, the crude product obtained by concentrating the reaction solution by a rotary evaporator was separated by column chromatography using a mixed solvent of petroleum ether and ethyl acetate in a volume ratio of 50:1 to obtain pure 3ba with a yield of 82%.
The nuclear magnetic data of 3ba are as follows:
1 H NMR(500MHz,DMSO-d 6 )δ7.49-7.48(m,1H),7.28(d,J＝2.0Hz,1H),7.253-7.23(m,5H),7.14-7.10(m,3H),7.04-7.03(m,1H),6.94-6.92(m,2H),6.29(d,J＝5.5Hz,1H),4.66(d,J＝5.5Hz,1H),4.26-4.20(m,2H),1.25(t,J＝7.0Hz,3H)ppm.
13 C NMR(125MHz,DMSO-d 6 )δ160.84,144.16,139.78,134.05,129.21,129.02,128.44,128.04,127.86,127.46,126.86,122.34,114.29,113.35,61.09,13.98ppm.
example 3
The reaction equation is as follows:
under the protection of nitrogen, compound 1c (5 mmol), 2a (20 mmol) and indium triflate (1.0 mmol) were added to the reactor, 50mL of dichloromethane was added, and the mixture was stirred at room temperature until the reaction was completed. After the reaction is completed, the crude product obtained by concentrating the reaction liquid by a rotary evaporator is separated by column chromatography by using a mixed solvent of petroleum ether and ethyl acetate in a volume ratio of 50:1, and the pure 3ca is obtained, and the yield is 37%.
The nuclear magnetic data of 3ca are as follows:
1 H NMR(500MHz,CDCl 3 )δ7.23-7.16(m,5H),7.15-7.08(m,5H),6.22-3.18(m,1H),4.40-4.21(m,2H),3.46-3.43(m,1H),1.50-1.41(m,3H),1.37-1.33(m,4H),0.85(t,J＝6.5Hz,3H)ppm.
13 C NMR(125MHz,CDCl 3 )δ161.85,146.81,141.96,138.91,134.57,129.47,129.07,128.37,127.88,127.58,126.77,114.38,114.14(d,J＝22.9Hz),68.89,61.26,37.81,37.04,21.83,18.65,14.18(d,J＝18.7Hz)ppm.
example 4
The reaction equation is as follows:
under nitrogen protection, compound 1d (5 mmol), 2b (20 mmol) and hafnium chloride (1.0 mmol) were added to the reactor, 50mL of dichloromethane was added, and the mixture was stirred at room temperature until the reaction was completed. After the reaction is finished, the crude product obtained by concentrating the reaction liquid by a rotary evaporator is separated by column chromatography by a mixed solvent of petroleum ether and ethyl acetate in a volume ratio of 50:1, and the pure 3db is obtained, and the yield is 84%.
The nuclear magnetic data of 3db are as follows:
1 H NMR(500MHz,DMSO-d 6 )δ7.65(d,J＝8.0Hz,1H),7.58(d,J＝1.5Hz,1H),7.45-7.39(m,5H),7.34-7.32(m,1H),6.08(d,J＝4.5Hz,1H),4.26(d,J＝5.0Hz,1H),3.73(s,3H),1.51(s,3H)ppm.
13 C NMR(125MHz,DMSO-d 6 )δ161.34,144.71,144.38,140.16,133.63,131.37,131.03,129.86(d,J＝19.5Hz),128.73(d,J＝6.3Hz),128.40,128.20,112.01,106.69,52.20,42.22,16.63ppm.
example 5
The reaction equation is as follows:
under nitrogen protection, compound 1d (5 mmol), 2c (10 mmol) and hafnium chloride (1.0 mmol) were added to the reactor, 50mL of dichloromethane was added, and the mixture was stirred at room temperature until the reaction was completed. After the reaction is completed, the crude product obtained by concentrating the reaction liquid by a rotary evaporator is separated by column chromatography by using a mixed solvent of petroleum ether and ethyl acetate in a volume ratio of 50:1, and pure 3dc is obtained, and the yield is 63%.
The nuclear magnetic data of 3dc are as follows:
1 H NMR(500MHz,DMSO-d 6 )δ8.07(s,1H),7.93(d,J＝8.0Hz,1H),7.89(d,J＝8.5Hz,1H),7.62-7.59(m,3H),7.54(t,J＝7.5Hz,1H),7.45-7.37(m,3H),6.92-6.86(m,5H),6.34(d,J＝4.5Hz,1H),4.97(s,1H),3.69(s,3H)ppm.
13 C NMR(125MHz,DMSO-d 6 )δ161.13,146.39,144.39,140.00,137.04,132.94,131.44,131.24,131.02,130.14,129.67,129.27,129.10,128.71,128.32(d,J＝4.5Hz),127.76,126.89,126.77,126.13,125.15,124.94,114.88,113.54,52.27,42.03ppm.
example 6
The reaction equation is as follows:
under the protection of nitrogen, 1d (5 mmol), 2d (20 mmol) and hafnium chloride (1.0 mmol) were added to the reactor, 50mL of dichloromethane was added, and the mixture was stirred at room temperature until the reaction was completed. After the reaction, the crude product obtained by concentrating the reaction solution by a rotary evaporator was separated by column chromatography using a mixed solvent of petroleum ether and ethyl acetate in a volume ratio of 50:1 to obtain pure 3dd with a yield of 72%.
The nuclear magnetic data of 3dd are as follows:
1 H NMR(500MHz,DMSO-d 6 )δ7.57(d,J＝8.5Hz,1H),7.50(d,J＝1.5Hz,1H),7.30-7.28(m,1H),7.18(d,J＝9.0Hz,2H),6.82(dd,J＝14.5,9.0Hz,4H),6.68(d,J＝8.5Hz,2H),6.23(d,J＝5.0Hz,1H),4.64(d,J＝5.0Hz,1H),3.75(s,3H),3.71(s,3H),3.63(s,3H)ppm.
13 C NMR(125MHz,DMSO-d 6 )δ161.26,159.15,157.90,146.40,144.80,139.82,131.25-130.992(m),130.31(d,J＝5.8Hz),129.89,129.56,128.47(d,J＝4.4Hz),127.78,126.14,113.60(d,J＝13.4Hz),113.33,110.66,55.03,54.80,52.28,42.59,30.70ppm.
from the above examples, it can be seen that the various and efficient syntheses of the polysubstituted 4H-pyrans are possible according to the present invention.
Claims (5)
1. A method for preparing a polysubstituted 4H-pyran compound, wherein the 4H-pyran compound has a structure shown in a formula I:
wherein R is 1 Any one selected from saturated alkyl, substituted alkyl, aryl and substituted aryl;
R 2 any one selected from methyl, ethyl and isopropyl;
R 3 、R 4 selected from saturated alkyl groups,Any two of the same or different substituted alkyl, aryl and substituted aryl;
the substituent of the substituted alkyl and the substituted aryl is any one of halogen atom, saturated alkyl, aryl, ester group, trifluoromethyl, nitro, hydroxyl and alkoxy;
the method comprises the following steps: under the protection of nitrogen, sequentially adding beta, gamma-unsaturated-alpha-keto ester, alkyne, lewis acid and solvent into a reactor, stirring at a certain temperature until the reaction is completed, and separating by column chromatography to obtain the polysubstituted 4H-pyran compound, wherein the chemical process is shown in a reaction formula II:
wherein the Lewis acid is selected from any one of hafnium chloride and indium triflate;
wherein the solvent is selected from any one of dichloromethane, chloroform and 1, 2-dichloroethane.
2. The preparation method according to claim 1, wherein the molar ratio of the beta, gamma-unsaturated-alpha-keto ester, alkyne and Lewis acid is 1.0 (1.0-10.0): 0.05-0.3.
3. The preparation method according to claim 1, wherein the reaction time is 0.5 to 6 hours.
4. The preparation method according to claim 1, wherein the reaction temperature is 0 to 60 ℃.
5. The preparation method according to claim 1, wherein the column chromatography is performed using a mixed solvent of petroleum ether and ethyl acetate.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104592181A (en) * | 2015-01-29 | 2015-05-06 | 华东师范大学 | 2-fluoro-polysubstituted-4H-pyran derivatives and preparation method thereof |
| CN107216300A (en) * | 2017-05-22 | 2017-09-29 | 中国科学院化学研究所 | The method of synthesis of chiral dihydropyran cyclics |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104592181A (en) * | 2015-01-29 | 2015-05-06 | 华东师范大学 | 2-fluoro-polysubstituted-4H-pyran derivatives and preparation method thereof |
| CN107216300A (en) * | 2017-05-22 | 2017-09-29 | 中国科学院化学研究所 | The method of synthesis of chiral dihydropyran cyclics |
Non-Patent Citations (5)
| Title |
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| Ethylenic acyl cyanides II: Conjugate addition of alkynylsilanes to ethylenic acyl cyanides;Abdelkebir Jellal 等;《Tetrahedron Letters》;第24卷(第13期);第1395-1398页 * |
| HfCl4-Catalyzed [4 + 2] Cycloaddition of β,γ-Unsaturated α-Keto Esters with Alkynes;Depeng Duan 等;《J. Org. Chem.》;第87卷;第5188−5198页 * |
| Jacqueline Ficini 等.Synthèse d'amino-2 alcoxy-6 γ pyrannes et de carbométhoxycyclobutanones par cycloaddition d'une ynamine sur les esters α-β éthyléniques.《Tetrahedron Letters》.1970,第11卷第885-888页. * |
| Nickel-Catalyzed [4 + 2] Cycloaddition of Enones with Alkynes;Ichiro Koyama 等;《J. AM. CHEM. SOC.》;第131卷;第1350-1351页 * |
| 吕健 等.不对称双酸催化3,4-二氢-2H-吡喃的反电子Hetero-Diels-Alder反应.《化学学报》.2012,第70卷第1518-1522页. * |
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