CN112441936B - Method for synthesizing enaminone compound - Google Patents
Method for synthesizing enaminone compound Download PDFInfo
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- CN112441936B CN112441936B CN201910794182.7A CN201910794182A CN112441936B CN 112441936 B CN112441936 B CN 112441936B CN 201910794182 A CN201910794182 A CN 201910794182A CN 112441936 B CN112441936 B CN 112441936B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C227/04—Formation of amino groups in compounds containing carboxyl groups
- C07C227/10—Formation of amino groups in compounds containing carboxyl groups with simultaneously increasing the number of carbon atoms in the carbon skeleton
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C227/38—Separation; Purification; Stabilisation; Use of additives
- C07C227/40—Separation; Purification
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
Abstract
A method of synthesizing enaminone compounds, the method comprising: mixing a substrate (I), a photosensitizer, a nitrogen source, a carbon source and a solvent, reacting for 20-36 h under the conditions of inert gas protection, temperature of 15-40 ℃ and illumination of a blue LED, and then carrying out post-treatment on a reaction solution to obtain an enamine ketone compound (II); the invention is safe and environment-friendly, does not generate waste gas and has low operation risk; the substrate has good adaptability, and various substituents can realize oxidative aromatization; the reaction condition is mild; the reaction has certain innovativeness and high atom economy, adopts a photocatalysis mode to replace the traditional heating mode, reduces energy consumption, and better accords with the modern green chemistry concept;
Description
(I) the technical field
The invention relates to a method for synthesizing enamine ketone compounds.
(II) background of the invention
Enamine ketone is also called enamine ketone or beta amino-alpha, beta-unsaturated ketone, because enamine ketone compound has a conjugated structure, it has nucleophilicity of enamine and electrophilicity of ketene, enamine ketone is used as a highly active and very useful organic intermediate in recent years, and is more and more widely applied to organic synthesis, especially in the synthesis of heterocyclic compounds, it is a key intermediate for synthesizing nitrogen-containing heterocyclic compounds such as pyridine, pyrrole, indole, oxazolidine, pyrimidone, quinoline, and the like; the method has very important application in synthesizing 3-aminosugar derivatives, alkaloid compounds and beta-amino derivatives. The existence of nitrogen atoms and oxygen atoms enables the enamine ketone compound to form a six-membered complex structure with main group metals or transition metals, so that the enamine ketone compound becomes a potential organic metal ligand, and the enamine ketone compound of a plurality of long-chain aliphatic hydrocarbons is often used as a dispersant in a lubricant. In addition, the enamine ketone compound has very wide physiological activity, the compound has more application in the pesticide and medicine field, especially, the arylamine enamine ketone compound has very good pharmacological action in the aspects of anticonvulsant, antimalarial, antivirus and treating cardiovascular diseases. Therefore, the research on the synthesis and the derivation of the enaminone compounds can obtain more enaminone compounds with various structures, and the method has important significance for developing and utilizing the applications of the enaminone compounds to a greater extent.
Currently, the Synthesis method of enaminone is mainly prepared by addition reaction of terminal alkyne, acyl chloride and ammonium salt as raw materials, and such reaction is generally completed by electrophilic addition reaction of organic amine and terminal alkyne (Synthesis,2003,18, 2815). However, there are several problems in this kind of reaction, firstly synthesizing the corresponding alkynone reagent, and meanwhile electrophilic addition to alkyne is generally difficult, and the yield of reaction is generally low, which also causes the method for synthesizing enaminone to be limited to synthesizing enaminone substrate with strong electron-withdrawing group. In addition, enaminones can be prepared by condensation reactions, and Henry et al prepare 2a (scheme 1) (j.am. chem. soc.,1958,80,1100) by reacting a beta-diketone with an amine or substituted amine, under conditions in which the substituents on the amine are generally smaller or have fewer substituents, and are generally less reactive and less productive for the more sterically hindered amines. According to the defects of the two methods and the synthesis idea of advocating green chemistry at present, the method adopts a photocatalysis method, takes cheap and easily-obtained olefin, tertiary amine and bromodifluoroacetic acid ethyl ester as initial raw materials and takes a catalytic amount of photosensitizer as a catalyst to synthesize the corresponding enaminone under the condition of no heating, has higher atom economy and low energy consumption, accords with the current time trend of green chemistry, and has larger application prospect.
Disclosure of the invention
Aiming at the defects of the prior art, the invention provides a general, simple and efficient method for synthesizing enamine ketone compounds.
The technical scheme of the invention is as follows:
a method of synthesizing enaminone compounds, the method comprising:
mixing a substrate (I), a photosensitizer, a nitrogen source, a carbon source and a solvent, reacting for 20-36 h (preferably 24h) under the conditions of inert gas protection, temperature of 15-40 ℃ (preferably 25 ℃) and illumination of a blue LED (15w), and then carrying out aftertreatment on a reaction solution to obtain an enaminone compound (II);
the mass ratio of the substrate (I), the photosensitizer, the nitrogen source and the carbon source is 1: 0.01-0.1: 2-4: 1-2, preferably 1: 0.05: 3: 1.5;
the volume usage amount of the solvent is 10-20 mL/mmol based on the substance amount of the substrate (I);
the photosensitizer is one or a mixture of two of a formula (III) and a formula (IV) in any proportion;
the nitrogen source is one or a mixture of two of triethylamine and tri-n-propylamine in any proportion;
the carbon source is ethyl bromodifluoroacetate;
the solvent is one or a mixed solvent of more than two of acetonitrile, tetrahydrofuran and 1, 4-dioxane in any proportion, preferably acetonitrile;
the post-treatment method comprises the following steps: after the reaction is finished, adding column chromatography silica gel (100-200 meshes) into the reaction solution, evaporating under reduced pressure to remove the solvent, and performing column chromatography separation, wherein the volume ratio of petroleum ether to ethyl acetate is 5:1 as eluent, collecting eluent containing target products, evaporating the solvent and drying to obtain an enamine ketone compound (II);
the reaction formula is as follows:
in the formula (I) or (II),
R1is phenyl, 2-naphthyl or 4-methylphenyl;
R2is ethyl or n-propyl;
the structural formula of the photosensitizer is as follows:
specifically, the enaminone compound (II) of the present invention is preferably one of the following compounds:
compared with the prior art, the invention has the beneficial effects that:
(1) the method is safe and environment-friendly, does not generate waste gas, and has low operation risk;
(2) the substrate has good adaptability, and various substituents can realize oxidative aromatization;
(3) the reaction condition is mild;
(4) the reaction has certain innovativeness and high atom economy, adopts a photocatalysis mode to replace the traditional heating mode, reduces energy consumption, and better conforms to the modern green chemistry concept.
(IV) detailed description of the invention
The present invention is further illustrated by the following examples, without limiting the scope of the invention:
example 1
2-vinylnaphthalene (0.3mmol, 0.0462g), photosensitizer (III) (0.015mmol, 0.00172g), triethylamine (0.9mmol, 0.0909g) and ethyl bromodifluoroacetate (0.45mmol, 0.0909g) were added to a 15mL sealed reaction tube, and 3mL of acetonitrile was added as a solvent. Then, under the irradiation of 15w Blue LED, reacting for 24h at 25 ℃ in a nitrogen environment, after the reaction is finished, adding two spoons (0.5g) of column chromatography silica gel (100 meshes and 200 meshes) into the reaction liquid, removing the solvent by reduced pressure distillation, and separating by column chromatography to obtain a pure product (petroleum ether/ethyl acetate-5: 1 is used as an eluent) shown in the structural formula. The material was a yellow liquid in 65% yield.
Characterization data:1H NMR(500MHz,CDCl3)δ8.06(s,1H),7.88(d,J＝8Hz,1H),7.63-7.57(m,4H),7.56(d,J＝8.5Hz,1H),7.51-7.47(m,1H),7.44-7.40(m,2H),7.37-7.34(m,1H),7.27-7.24(m,1H),7.09(t,J＝7.5Hz,1H),6.43(d,J＝7.5Hz,1H),5.72(s,1H),2.65(s,1H).
13C NMR(125MHz,CDCl3)δ146.49,143.54,139.77,138.42,135.13,133.85,133.79,133.12,130.00,129.73,129.08,129.02,128.85,128.29,127.93,127.83,126.38,126.18,125.75,125.15,123.92,123.44,74.26.
example 2
2-vinylnaphthalene (0.3mmol, 0.0462g), photosensitizer (IV) (0.015mmol, 0.0176g), triethylamine (0.9mmol, 0.0909g) and ethyl bromodifluoroacetate (0.45mmol, 0.0909g) were added to a 15mL sealed reaction tube, followed by 3mL acetonitrile as a solvent. Then, under the irradiation of 15w Blue LED, reacting for 24h under the condition of 25 ℃ and nitrogen atmosphere, after the reaction is finished, adding two-spoon column chromatography silica gel (100-200 meshes), removing the solvent by reduced pressure distillation, and separating by column chromatography to obtain the pure product (taking petroleum ether/ethyl acetate ═ 5:1 as an eluent) shown in the structural formula. The material was a yellow liquid in 51% yield.
Characterization data:1H NMR(500MHz,CDCl3)δ8.01(s,1H),7.79(d,J＝8.5Hz,1H),7.64(d,J＝7.5Hz,1H),7.62-7.57(m,3H),7.42-7.36(m,2H),7.27-7.24(m,1H),7.14(dd,J1＝8.5Hz,J2＝2.5Hz,1H),7.08-7.05(m,1H),6.82(d,J＝2.5Hz,1H),6.37(d,J＝7.5Hz,1H),5.74(s,1H),3.70(s,3H),2.30(s,1H).
13C NMR(126MHz,CDCl3)δ157.93,146.72,141.38,139.94,138.62,135.66,135.15,132.77,130.01,129.70,129.23,129.16,128.82,128.57,127.90,127.87,125.13,123.69,123.45,117.75,105.56,74.35,55.07.
example 3
2-vinylnaphthalene (0.3mmol, 0.0462g), photosensitizer (III) (0.003mmol, 0.0017g), triethylamine (0.9mmol, 0.0909g) and ethyl bromodifluoroacetate (0.45mmol, 0.0909g) were added to a 15mL blocked reaction tube, followed by 3mL acetonitrile as a solvent. And then, reacting for 24 hours under the condition of 25 ℃ and nitrogen atmosphere under the irradiation of 15w Blue LED, adding two-spoon column chromatography silica gel (100-200 meshes) into the reaction liquid after the reaction is finished, removing the solvent through reduced pressure distillation, and separating by column chromatography to obtain a pure product (taking petroleum ether/ethyl acetate-5: 1 as an eluent) shown in the structural formula. The material was a yellow liquid in 60% yield.
Characterization data:1H NMR(500MHz,CDCl3)δ8.41(s,1H),7.66(d,J＝7Hz,1H),7.62-7.59(m,3H),7.40-7.36(m,2H),7.32-7.27(m,3H),7.18-7.14(m,1H),7.09(t,J＝7.5Hz,1H),6.40(d,J＝8Hz,1H),5.80(s,1H),2.22(s,1H).
13C NMR(125MHz,CDCl3)δ159.18(d,J＝225Hz),146.58,144.02,139.45,138.15,136.14,135.60(d,J＝3.75Hz),133.67(d,J＝2.5Hz),129.92,129.67,129.21,129.15,129.01,128.35,128.09,125.83(d,J＝8.75Hz),125.23,123.68,123.26,123.13,122.28(d,J＝3.75Hz),116.56(d,J＝6.25Hz),109.53(d,J＝20Hz),74.38.
example 4
2-vinylnaphthalene (0.3mmol, 0.0462g), photosensitizer (III) (0.03mmol, 0.0344g), triethylamine (0.9mmol, 0.0909g), and ethyl bromodifluoroacetate (0.45mmol, 0.0909g) were added to a 15mL blocked reaction tube, followed by 3mL acetonitrile as a solvent. Then, under the irradiation of 15w Blue LED, reacting for 24h under the condition of 25 ℃ and nitrogen atmosphere, after the reaction is finished, adding two-spoon column chromatography silica gel (100-200 meshes), removing the solvent by reduced pressure distillation, and separating by column chromatography to obtain the pure product (taking petroleum ether/ethyl acetate ═ 5:1 as an eluent) shown in the structural formula. The material was a yellow liquid in 64% yield.
Characterization data:1H NMR(500MHz,CDCl3)δ8.06(s,1H),7.76(d,J＝9Hz,1H),7.65-7.60(m,5H),7.55(dd,J1＝8.5Hz,J2＝2Hz,1H),7.39-7.33(m,2H),7.29-7.26(m,1H),7.10-7.07(m,1H),6.36(d,J＝7.5Hz,1H),5.76(d,J＝9Hz,1H),2.21(d,J＝9.5Hz,1H).
13C NMR(125MHz,CDCl3)δ146.53,144.07,139.43,137.61,136.28,135.21,133.06,131.60,129.98,129.88,129.69,129.36,129.32,129.19,129.09,128.57,128.39,128.27,125.19,123.85,123.71,120.71,74.37.
example 5
2-vinylnaphthalene (0.3mmol, 0.0462g), photosensitizer (III) (0.015mmol, 0.0172g), tri-n-propylamine (0.6mmol, 0.0858g), and ethyl bromodifluoroacetate (0.45mmol, 0.0909g) were added to a 15mL sealed reaction tube, followed by 3mL acetonitrile as a solvent. And then, reacting for 24 hours under the condition of 25 ℃ and nitrogen atmosphere under the irradiation of 15w Blue LED, adding two-spoon column chromatography silica gel (100-200 meshes) into the reaction liquid after the reaction is finished, removing the solvent through reduced pressure distillation, and separating by column chromatography to obtain a pure product (taking petroleum ether/ethyl acetate-5: 1 as an eluent) shown in the structural formula. The material was a yellow liquid in 57% yield.
Characterization data:1H NMR(500MHz,CDCl3)δ8.05(s,1H),7.81(d,J＝8.5Hz,1H),7.65-7.60(m,4H),7.42-7.37(m,2H),7.34-7.32(m,1H),7.29(s,1H),7.27-7.24(m,1H),7.09-7.06(m,1H),6.36(d,J＝8Hz,1H),5.76(s,1H),2.42(s,3H),2.28(s,1H).
13C NMR(125MHz,CDCl3)δ146.56,142.65,139.98,138.64,136.03,135.26,134.05,133.30,131.41,130.08,129.82,129.13,129.07,128.87,128.17,128.03,127.86,127.81,125.46,125.14,123.72,123.46,74.39,21.90.
example 6
2-vinylnaphthalene (0.3mmol, 0.0462g), photosensitizer (III) (0.015mmol, 0.0172g), tri-n-propylamine (1.2mmol, 0.1716g), and ethyl bromodifluoroacetate (0.45mmol, 0.0909g) were added to a 15mL sealed reaction tube, followed by 3mL acetonitrile as a solvent. Then, under the irradiation of 15w Blue LED, reacting for 24h under the condition of 25 ℃ and nitrogen atmosphere, after the reaction is finished, adding two-spoon column chromatography silica gel (100-200 meshes), removing the solvent by reduced pressure distillation, and separating by column chromatography to obtain the pure product (taking petroleum ether/ethyl acetate ═ 5:1 as an eluent) shown in the structural formula. The material was a yellow liquid in 62% yield.
Characterization data:1H NMR(500MHz,CDCl3)δ8.01(s,1H),7.85(d,J＝7.5Hz,1H),7.62-7.57(m,3H),7.51(d,J＝8.5Hz,1H),7.46-7.43(m,1H),7.41-7.37(m,2H),7.35-7.33(m,1H),7.16(d,J＝2.5Hz,1H),6.61(dd,J1＝8.5Hz,J2＝2.5Hz,1H),6.30(d,J＝9Hz,1H),5.66(s,1H),3.77(s,3H),2.54(s,1H).
13C NMR(125MHz,CDCl3)δ159.98,148.51,143.67,138.63,135.24,134.00,132.63,132.53,132.35,130.18,129.91,129.17,129.11,128.34,127.82,126.22,126.16,125.41,124.40,123.80,115.21,110.27,77.35,77.09,76.84,74.30,55.43.
example 7
2-vinylnaphthalene (0.3mmol, 0.0462g), photosensitizer (III) (0.015mmol, 0.0172g), tri-n-propylamine (0.9mmol, 0.1287g) and ethyl bromodifluoroacetate (0.3mmol, 0.0606g) were added to a 15mL sealed reaction tube, and 3mL of acetonitrile was added as a solvent. Then, under the irradiation of 15w Blue LED, reacting for 24h under the condition of 25 ℃ and nitrogen atmosphere, after the reaction is finished, adding two-spoon column chromatography silica gel (100-200 meshes), removing the solvent by reduced pressure distillation, and separating by column chromatography to obtain the pure product (taking petroleum ether/ethyl acetate ═ 5:1 as an eluent) shown in the structural formula. The material was a yellow liquid in 51% yield.
Characterization data:1H NMR(500MHz,CDCl3)δ8.08(s,1H),7.90(d,J＝8Hz,1H),7.65-7.60(m,3H),7.56-7.49(m,3H),7.43-7.40(m,1H),7.39-7.32(m,2H),7.21(dd,J1＝8Hz,J2＝1Hz,1H),6.28(d,J＝2Hz,1H),5.72(s,1H),2.36(s,1H).
13C NMR(125MHz,CDCl3)δ144.71,143.51,141.59,137.78,134.81,134.55,134.05,133.79,133.37,129.79,129.54,129.29,129.23,128.34,128.22,127.86,126.59,126.47,126.22,126.13,124.09,123.72,73.91
example 8
2-vinylnaphthalene (0.3mmol, 0.0462g), photosensitizer (III) (0.015mmol, 0.0172g), tri-n-propylamine (0.9mmol, 0.1287g), and ethyl bromodifluoroacetate (0.6mmol, 0.1212g) were added to a 15mL sealed reaction tube, followed by 3mL acetonitrile as a solvent. Then, under the irradiation of 15w Blue LED, reacting for 24h under the condition of 25 ℃ and nitrogen atmosphere, after the reaction is finished, adding two-spoon column chromatography silica gel (100-200 meshes), removing the solvent by reduced pressure distillation, and separating by column chromatography to obtain the pure product (taking petroleum ether/ethyl acetate ═ 5:1 as an eluent) shown in the structural formula. The material was a yellow liquid in 64% yield.
Characterization data:1H NMR(500MHz,CDCl3)δ8.07(s,1H),7.88(d,J＝8Hz,1H),7.62(d,J＝7.5Hz,1H),7.47-7.42(m,1H),7.41-7.34(m,3H),7.22-7.16(m,2H),7.07-7.04(m,1H),6.30(d,J＝8Hz,1H),5.70(d,J＝8.5Hz,1H),2.32-2.32(d,J＝3.5Hz,1H),1.92(s,3H).
13C NMR(125MHz,CDCl3)δ217.94,146.41,143.70,139.91,137.71,136.97,135.09,133.43,133.29,133.19,130.42,130.06,129.23,128.46,128.23,127.99,126.64,126.39,126.04,125.86,125.11,123.79,123.01,74.47,19.61.
example 9
Styrene (0.3mmol, 0.0312g), photosensitizer (III) (0.015mmol, 0.0172g), triethylamine (0.9mmol, 0.0909g) and ethyl bromodifluoroacetate (0.45mmol, 0.0909g) were added to a 15mL sealed reaction tube, followed by 3mL tetrahydrofuran as a solvent. Then, under the irradiation of 15w Blue LED, reacting for 24h under the condition of 25 ℃ and nitrogen atmosphere, after the reaction is finished, adding two-spoon column chromatography silica gel (100-200 meshes), removing the solvent by reduced pressure distillation, and separating by column chromatography to obtain the pure product (taking petroleum ether/ethyl acetate ═ 5:1 as an eluent) shown in the structural formula. The material was a yellow liquid in 47% yield.
Characterization data:1H NMR(500MHz,CDCl3)δ8.10(s,1H),7.90(d,J＝8Hz,1H),7.65(d,J＝7.5Hz,1H),7.57(d,J＝8Hz,1H),7.52-7.47(m,2H),7.42-7.39(m,2H),7.29-7.22(,2H),7.19(d,J＝8.5Hz,1H),7.11(t,J＝7.5Hz,1H),6.46(d,J＝7.5Hz,1H),5.78(d,J＝6.5Hz,1H),2.48(d,J＝7Hz,3H),2.47(s,1H).
13C NMR(126MHz,CDCl3)δ146.50,143.57,139.93,138.70,138.33,135.09,134.11,133.97,133.18,130.61,130.35,128.95,128.57,128.29,127.94,127.02,126.75,126.54,126.18,125.78,125.15,123.85,123.61,77.29,77.03,76.78,74.43,21.52.
example 10
Styrene (0.3mmol, 0.0312g), photosensitizer (III) (0.015mmol, 0.0172g), triethylamine (0.9mmol, 0.0909g) and ethyl bromodifluoroacetate (0.45mmol, 0.0909g) were added to a 15mL tube-sealed reaction tube, and 3mL of 1, 4-dioxane was added as a solvent. Then, under the irradiation of 15w Blue LED, reacting for 24h under the condition of 25 ℃ and nitrogen atmosphere, after the reaction is finished, adding two-spoon column chromatography silica gel (100-200 meshes), removing the solvent by reduced pressure distillation, and separating by column chromatography to obtain the pure product (taking petroleum ether/ethyl acetate ═ 5:1 as an eluent) shown in the structural formula. The material was a yellow liquid in 45% yield.
Characterization data:1H NMR(500MHz,CDCl3)δ8.11(s,1H),7.91-7.86(3H),7.65(d,J＝7.5Hz,1H),7.55(d,J＝8Hz,1H),7.52-7.49(m,2H),7.44-7.39(m,2H),7.30-7.27(m,1H),7.11(t,J＝7.5Hz,1H),6.37(d,J＝7.5Hz,1H),5.75(d,J＝8Hz,1H)2.39(d,J＝8.5Hz,1H).
13C NMR(125MHz,CDCl3)δ146.61,143.59,142.50,139.33,135.15,133.48,133.13,132.07,130.68,130.42,130.29(dd,J1＝65Hz,J2＝32.5Hz),129.10,128.49,128.35,126.62,126.14(dd,J1＝7.5Hz,J2＝3.75Hz),126.07,125.94,125.40,125.37,124.56,123.20,74.26.
example 11
Styrene (0.3mmol, 0.0312g), photosensitizer (III) (0.015mmol, 0.0172g), triethylamine (0.9mmol, 0.0909g) and ethyl bromodifluoroacetate (0.45mmol, 0.0909g) were added to a 15mL sealed reaction tube, followed by 3mL acetonitrile as a solvent. Then, under the irradiation of 15w Blue LED, reacting for 24h under the condition of 15 ℃ and nitrogen atmosphere, after the reaction is finished, adding two-spoon column chromatography silica gel (100-200 meshes), removing the solvent by reduced pressure distillation, and separating by column chromatography to obtain the pure product (taking petroleum ether/ethyl acetate ═ 5:1 as an eluent) shown in the structural formula. The material was a yellow liquid in 58% yield.
Characterization data:1H NMR(500MHz,CDCl3)δ8.06(s,1H),7.88(d,J＝8Hz,1H),7.63-7.57(m,4H),7.56(d,J＝8.5Hz,1H),7.51-7.47(m,1H),7.44-7.40(m,2H),7.37-7.34(m,1H),7.27-7.24(m,1H),7.09(t,J＝7.5Hz,1H),6.43(d,J＝7.5Hz,1H),5.72(s,1H),2.65(s,1H).
13C NMR(125MHz,CDCl3)δ146.49,143.54,139.77,138.42,135.13,133.85,133.79,133.12,130.00,129.73,129.08,129.02,128.85,128.29,127.93,127.83,126.38,126.18,125.75,125.15,123.92,123.44,74.26.
example 12
4-methylstyrene (0.3mmol, 0.0354g), photosensitizer (III) (0.015mmol, 0.0172g), tri-n-propylamine (0.9mmol, 0.1287g) and ethyl bromodifluoroacetate (0.45mmol, 0.0909g) were charged into a 15mL sealed reaction tube, and 3mL of acetonitrile was added as a solvent. And then, reacting for 24 hours under the condition of 40 ℃ and nitrogen atmosphere under the irradiation of 15w Blue LED, adding two-spoon column chromatography silica gel (100-200 meshes) into the reaction liquid after the reaction is finished, removing the solvent through reduced pressure distillation, and separating by column chromatography to obtain a pure product (taking petroleum ether/ethyl acetate-5: 1 as an eluent) shown in the structural formula. The material was a yellow liquid in 49% yield.
Characterization data:1H NMR(500MHz,CDCl3)δ8.01(s,1H),7.79(d,J＝8.5Hz,1H),7.64(d,J＝7.5Hz,1H),7.62-7.57(m,3H),7.42-7.36(m,2H),7.27-7.24(m,1H),7.14(dd,J1＝8.5Hz,J2＝2.5Hz,1H),7.08-7.05(m,1H),6.82(d,J＝2.5Hz,1H),6.37(d,J＝7.5Hz,1H),5.74(s,1H),3.70(s,3H),2.30(s,1H).
13C NMR(126MHz,CDCl3)δ157.93,146.72,141.38,139.94,138.62,135.66,135.15,132.77,130.01,129.70,129.23,129.16,128.82,128.57,127.90,127.87,125.13,123.69,123.45,117.75,105.56,74.35,55.07.
example 13
4-methylstyrene (0.3mmol, 0.0354g), photosensitizer (III) (0.015mmol, 0.0172g), tri-n-propylamine (0.9mmol, 0.1287g), and ethyl bromodifluoroacetate (0.45mmol, 0.0909g) were added to a 15mL sealed reaction tube, followed by 3mL acetonitrile as a solvent. Then, under the irradiation of 15w Blue LED, reacting for 20h under the condition of 25 ℃ and nitrogen atmosphere, after the reaction is finished, adding two-spoon column chromatography silica gel (100-200 meshes), removing the solvent by reduced pressure distillation, and separating by column chromatography to obtain the pure product (taking petroleum ether/ethyl acetate ═ 5:1 as an eluent) shown in the structural formula. The material was a yellow liquid in 63% yield.
Characterization data:1H NMR(500MHz,CDCl3)δ8.41(s,1H),7.66(d,J＝7Hz,1H),7.62-7.59(m,3H),7.40-7.36(m,2H),7.32-7.27(m,3H),7.18-7.14(m,1H),7.09(t,J＝7.5Hz,1H),6.40(d,J＝8Hz,1H),5.80(s,1H),2.22(s,1H).
13C NMR(125MHz,CDCl3)δ159.18(d,J＝225Hz),146.58,144.02,139.45,138.15,136.14,135.60(d,J＝3.75Hz),133.67(d,J＝2.5Hz),129.92,129.67,129.21,129.15,129.01,128.35,128.09,125.83(d,J＝8.75Hz),125.23,123.68,123.26,123.13,122.28(d,J＝3.75Hz),116.56(d,J＝6.25Hz),109.53(d,J＝20Hz),74.38.
example 14
4-methylstyrene (0.3mmol, 0.0354g), photosensitizer (III) (0.015mmol, 0.0172g), tri-n-propylamine (0.9mmol, 0.1287g) and ethyl bromodifluoroacetate (0.45mmol, 0.0909g) were charged into a 15mL sealed reaction tube, and 3mL of acetonitrile was added as a solvent. And then, reacting for 36h under the condition of 25 ℃ and nitrogen atmosphere under the irradiation of 15w Blue LED, adding two-spoon column chromatography silica gel (100-200 meshes) into the reaction liquid after the reaction is finished, removing the solvent through reduced pressure distillation, and separating by column chromatography to obtain a pure product (taking petroleum ether/ethyl acetate-5: 1 as an eluent) shown in the structural formula. The material was a yellow liquid in 65% yield.
Characterization data:1H NMR(500MHz,CDCl3)δ8.06(s,1H),7.76(d,J＝9Hz,1H),7.65-7.60(m,5H),7.55(dd,J1＝8.5Hz,J2＝2Hz,1H),7.39-7.33(m,2H),7.29-7.26(m,1H),7.10-7.07(m,1H),6.36(d,J＝7.5Hz,1H),5.76(d,J＝9Hz,1H),2.21(d,J＝9.5Hz,1H).
13C NMR(125MHz,CDCl3)δ146.53,144.07,139.43,137.61,136.28,135.21,133.06,131.60,129.98,129.88,129.69,129.36,129.32,129.19,129.09,128.57,128.39,128.27,125.19,123.85,123.71,120.71,74.37.
meanwhile, the product enaminone of the invention has multiple uses, as shown in the following, wherein 2a is an intermediate which can be used for synthesizing trandolapril medicaments.
2a Synthesis procedure (general formula)
Dissolving the product enamine ketone compound (0.3mmol) obtained by the invention in 3ml of methanol, adding (0.45mmol, 0.055g)9-BBN (9-boron bicyclo (3,3,1) -nonane), stirring for 24h at room temperature, adding two-spoon column chromatography silica gel (100-200 meshes) into the reaction liquid after the reaction is finished, removing the solvent by reduced pressure distillation, and separating by column chromatography to obtain the pure product (taking petroleum ether/ethyl acetate ═ 10:1 as an eluent) shown in the structural formula to obtain the enamine ketone compound (2 a).
Synthesis of specific substances such as:
dissolving the product (Z) -4- (diethylamino) -2-oxo-4-phenylbut-3-enoic acid ethyl ester (0.3mmol,0.082g) in 3ml of methanol, adding (0.45mmol, 0.055g)9-BBN (9-borabicyclo (3,3,1) -nonane), stirring at room temperature for 24h, adding two-spoon column chromatography silica gel (100 meshes and 200 meshes) to the reaction solution after the reaction is finished, removing the solvent by reduced pressure distillation, and separating by column chromatography to obtain a pure product (petroleum ether/ethyl acetate ═ 10:1 as an eluent) shown in the structural formula to obtain the ketene compound (E) -2-oxo-4-phenylbut-3-enoic acid ethyl ester.
Dissolving the product (Z) -4- (dipropylamino) -2-oxo-4- (p-tolyl) ethyl but-3-enoate (0.3mmol,0.0951g) in 3ml of methanol, adding (0.45mmol, 0.055g)9-BBN (9-borabicyclo (3,3,1) -nonane), stirring at room temperature for 24h, adding two-spoon column chromatography silica gel (100-.
The product ethyl (Z) -4- (dipropylamino) -4- (naphthalen-2-yl) -2-oxobut-3-enoate (0.3mmol,0.106g) was dissolved in 3ml of methanol, followed by addition (0.45mmol, 0.055g) of 9-BBN (9-borabicyclo (3,3,1) -nonane), stirring for 24h at room temperature, adding two spoons of column chromatography silica gel (100-200 mesh) into the reaction solution after the reaction is finished, and removing the solvent by reduced pressure distillation, and separating by column chromatography to obtain a pure product (petroleum ether/ethyl acetate 10:1 is used as an eluent) shown as the structural formula, so as to obtain the ketene compound (E) -4- (naphthalene-2-yl) -2-oxo-butyl-3-ethyl enoate.
The product ethyl (Z) -4- (diethylamino) -4- (naphthalen-2-yl) -2-oxobut-3-enoate (0.3mmol,0.106g) was dissolved in 3ml of methanol, and 9-BBN (9-borabicyclo (3,3,1) -nonane) (0.45mmol, 0.055g) was added, stirring for 24h at room temperature, adding two spoons of column chromatography silica gel (100-200 mesh) into the reaction solution after the reaction is finished, and removing the solvent by reduced pressure distillation, and separating by column chromatography to obtain a pure product (petroleum ether/ethyl acetate 10:1 is used as eluent) shown in the structural formula to obtain the ketene compound (E) -4- (naphthalene-2-yl) -2-oxo-butyl-3-ethyl enoate.
Claims (4)
1. A method for synthesizing an enaminone compound (II), the method comprising:
mixing a substrate (I), a photosensitizer, a nitrogen source, a carbon source and a solvent, reacting for 20-36 h under the conditions of inert gas protection, temperature of 15-40 ℃ and illumination of a blue LED, and then carrying out post-treatment on a reaction solution to obtain an enaminone compound (II);
the mass ratio of the substrate (I), the photosensitizer, the nitrogen source and the carbon source is 1: 0.01-0.1: 2-4: 1-2;
the photosensitizer is one or a mixture of two of a formula (III) and a formula (IV) in any proportion;
the nitrogen source is one or a mixture of two of triethylamine and tri-n-propylamine in any proportion;
the carbon source is ethyl bromodifluoroacetate;
the solvent is one or a mixed solvent of more than two of acetonitrile, tetrahydrofuran and 1, 4-dioxane in any proportion;
the reaction formula is as follows:
in the formula (I) or (II),
R1is phenyl, 2-naphthyl or 4-methylphenyl;
R2is ethyl or n-propyl.
2. The method for synthesizing enaminone compounds (II) according to claim 1, wherein the ratio of the amounts of the substrate (I), the photosensitizer, the nitrogen source and the carbon source is 1: 0.05: 3: 1.5.
3. The method for synthesizing enaminones (II) according to claim 1, wherein the volume usage of the solvent is 10 to 20mL/mmol based on the substance of the substrate (I).
4. The process for the synthesis of enaminone compounds (II) according to claim 1, wherein the work-up is carried out by: and after the reaction is finished, adding column chromatography silica gel into the reaction liquid, distilling off the solvent under reduced pressure, performing column chromatography separation, eluting by using a mixed liquid of petroleum ether and ethyl acetate in a volume ratio of 5:1 as an eluent, collecting eluent containing the target product, distilling off the solvent and drying to obtain the enamine ketone compound (II).
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