CN117088846A - Synthesis method of chromone compound - Google Patents

Synthesis method of chromone compound Download PDF

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CN117088846A
CN117088846A CN202311061080.7A CN202311061080A CN117088846A CN 117088846 A CN117088846 A CN 117088846A CN 202311061080 A CN202311061080 A CN 202311061080A CN 117088846 A CN117088846 A CN 117088846A
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compound
reaction
chromone
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yield
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王雪松
李友宾
马健婷
吴女江
唐瑶
徐俊裕
王燕
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Hainan Medical College
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D335/00—Heterocyclic compounds containing six-membered rings having one sulfur atom as the only ring hetero atom
    • C07D335/04—Heterocyclic compounds containing six-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D335/06—Benzothiopyrans; Hydrogenated benzothiopyrans
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C07D311/22—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4
    • C07D311/26—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3
    • C07D311/28—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3 with aromatic rings attached in position 2 only
    • C07D311/30—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3 with aromatic rings attached in position 2 only not hydrogenated in the hetero ring, e.g. flavones
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
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    • Y02P20/584—Recycling of catalysts

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Abstract

The invention discloses a synthesis method of chromone compounds. The synthesis route of the invention takes alcohol as a substrate and 2-halogenated alpha, beta-unsaturated alkynone compound as a raw material, and the chromone compound is synthesized by the action of alkali, and the synthesis mode of the thiochromone compound is as follows: the method solves the problem that raw material alcohol is difficult to purchase and the cost of purchasing raw material alcohol is high, and can be reduced after the raw material alcohol is magnetically stirred and reacts for 2 hours at room temperature by taking the compound 1q of 0.5mmol and the furfuryl mercaptan of 0.7mmo as reaction substrates in the experimental process and adding one drop of tributylphosphine as a catalyst and a proper amount of dimethyl sulfoxide as a solvent. This helps laboratories and researchers to save costs and allows more efficient use of research expenses; the amount of raw alcohol used can be reduced by optimizing the synthesis route and improving the synthesis efficiency. This helps to reduce reliance on limited resources, improve laboratory sustainability, and reduce environmental impact.

Description

Synthesis method of chromone compound
Technical Field
The invention relates to the technical field of organic synthesis, in particular to a synthesis method of chromone compounds.
Background
Chromone (also known as chromone) is a heterocyclic compound having a benzopyrone backbone. Chromone derivatives are widely present in plants as a secondary metabolite, have activity in many plant growth cycles such as growth regulation, indoleacetic acid oxidation and dormancy inhibition, and exhibit cytokinin-type behavior and stimulate oxygen uptake in plant tissues, and are less toxic to mammalian cells. Chromone derivatives also exhibit a variety of biological activities, such as antibacterial, antioxidant, anticancer, antifungal, antitumor, antiviral, and anti-inflammatory, among others. The chromone derivative is regarded as an attractive new medicine synthesis source because of effective activity and low toxicity, and the thiochromone is a thiohomolog of the chromone, namely, the alpha, beta-unsaturated cyclic ketone is taken as a main structure, and the unsaturated cyclic ketone structure has stronger tension and can be subjected to M ichae addition reaction with peptides, enzymes and the like containing sulfhydryl groups in organisms to keep the stability of the ring, so that the functions of active peptides and enzymes are obviously influenced, and the active peptides and enzymes have wide pharmacological activities such as oxidation resistance, tyrosinase activity inhibition and the like. The characteristics lead the synthesis of the thiochromone compounds and the development of the bioactivity of the thiochromone compounds to be a great point in the field of new medicine development. Thiochromones exist in various forms in plants in nature, but unlike chromones, thiochromones have not been isolated from natural products and are reported in the literature to be mainly synthesized.
For example, patent publication No. CN115536653A and the combination of the prior art have the following defects that the prior synthesis method takes chromone-3-formaldehyde as a raw material, the compound is not a popular chemical, the market price is high, and the cost is high. The synthesis of the method mainly takes o-hydroxyacetophenone as a raw material, and is prepared by formylation of phosphorus oxychloride, wherein the phosphorus oxychloride has pungent smell and is easy to react violently when meeting water, and the industrialized application of the method has higher requirements on environment and facilities; the existing method has high yield and strict requirements on reaction conditions, and generally needs dangerous chemical reagents, high temperature, illumination and other conditions, so that the operation is difficult, potential safety hazards exist, and the amplification is difficult; the method which is easy to operate has low yield (below 60 percent) and is uneconomical. The batch processing amount of the existing method is only gram level or even milligram level, and the existing method has a large distance from the mass production. Therefore, breaks through the conventional thinking, designs and explores a synthesis method which is simple and convenient to operate, low in cost and high in yield, and is a main direction of future chromone compound synthesis research.
Disclosure of Invention
(one) solving the technical problems
Aiming at the defects of the prior art, the invention aims to provide a synthesis method of chromone compounds, the experiment provides a new thought for constructing a 3-position functionalized chromone skeleton through a plurality of different substrates, and meanwhile, a simple synthesis method is found for alcohol compounds which are difficult to obtain, the synthesis method can be prepared through a chemical method, and a plurality of chromone compounds are obtained through the experiment.
(II) technical scheme
The invention provides a technical scheme for realizing the purpose, and the technical scheme is that the synthesis method of the chromone compound adopts the following steps that alcohol is used as a substrate, 2-halogenated alpha, beta-unsaturated acetylenic ketone compound is used as a raw material, and the chromone compound is synthesized by the action of alkali, wherein the synthesis mode of the chromone compound is as follows:
taking 0.5mmol of compound 1q and 0.7mmol of furfuryl mercaptan as reaction substrates in the experimental process, adding one drop of tributylphosphine as a catalyst and a proper amount of dimethyl sulfoxide as a solvent, magnetically stirring at room temperature for reaction for 2 hours, directly adding 1mmol of double-equivalent potassium carbonate into the same reaction system, adding a nitrogen protection device, continuously pumping out air for five times to remove oxygen, placing a round-bottom flask in an oil bath pot at 105 ℃ for magnetically stirring for reaction for 10 hours, and separating yellow solid compound 3q by silica gel column chromatography, wherein the yield is 91%.
As a preferable scheme, the synthesis mode of the 3-substituted chromone compound in the chromone compound is as follows:
taking 0.5mmol of compound 1p and 0.7mmol of allyl mercaptan as reaction substrates in the experimental process, adding one drop of tributylphosphine as a catalyst and a proper amount of dimethyl sulfoxide as a solvent, magnetically stirring at room temperature for reaction for 2 hours, directly adding 1mmol of double-equivalent potassium carbonate into the same reaction system, adding a nitrogen protection device, continuously pumping out gas for five times to remove oxygen, placing a round-bottom flask into an oil bath pot at 105 ℃ for magnetically stirring for reaction for 10 hours, and separating eluent by silica gel column chromatography: PE/EtOAc=10/1, 6/1, v/v yellow liquid, compound 3p, 92% yield.
As a preferable scheme, the synthesis mode of the chromone compound 3o is as follows:
taking 0.5mmol of compound 1o and 0.7mmol of allyl alcohol as reaction substrates in the experimental process, adding one drop of tributylphosphine as a catalyst and a proper amount of dimethyl sulfoxide as a solvent, magnetically stirring and reacting for 2 hours at room temperature, directly adding 1mmol of double-equivalent potassium carbonate into the same reaction system, adding a nitrogen protection device, continuously pumping out and discharging gas for five times to remove oxygen, placing a round-bottom flask into an oil bath pot at 105 ℃ for magnetically stirring and reacting for 10 hours, separating by silica gel column chromatography, and eluting with an eluent: PE/EtOAc=10/1, 6/1, v/v yellow solid, compound 3o, 89% yield.
As a preferable scheme, the synthesis of the chromone compound comprises a 3-thiophene chromone compound, and the reaction mode is as follows:
2-acetylthiophene (5 mmol), 10 times sodium borohydride (25 mmol) and methanol as solvent are added into a 100ml round bottom flask, and the corresponding alcohol can be produced by magnetic stirring reaction for 3h under ice bath condition because the oxidation-reduction reaction is relatively severe. After the reaction was completed, the solvent methanol was removed by concentrating under reduced pressure, the filtrate was repeatedly extracted 3 times with ethyl acetate and water, and the upper ethyl acetate layer was collected for thin layer chromatography TLC, and spots of different heights appeared on TLC by the difference in polarity of the compounds. Observing that the obtained raw material alcohol is a compound with relatively large polarity in a dark box type ultraviolet analyzer, concentrating the filtrate collected after extraction again under reduced pressure, removing ethyl acetate, separating residues by column chromatography to remove insoluble substances such as salts generated in the reaction process, and finally obtaining a compound (S/R) -1- (2-thiophene) ethanol, and eluting with an eluent: PE/EtOAc=3/1, 1/1, v/v to give a pale yellow liquid with 97% yield of the compound; then 0.5mmol of compound 1 and 0.7mmol of (S/R) -1- (2-thiophene) ethanol are taken as reaction substrates in the experimental process, one drop of tributylphosphine is taken as a catalyst, a proper amount of dimethyl sulfoxide is taken as a solvent, after magnetically stirring and reacting for 2 hours at room temperature, 1mmol of twice equivalent potassium carbonate is directly added into the same reaction system, a nitrogen protection device is added, and continuously pumping out air for five times to remove oxygen, after the round bottom flask is placed in an oil bath pot at 105 ℃ for magnetically stirring and reacting for 10 hours, silica gel column chromatography separation is carried out, and eluent: PE/EtOAc=10/1, 6/1, v/v, yellow solid, compound 3m, 92% yield.
Preferably, the selected solvent may be N, N-dimethylformamide, N-methylpyrrolidone, dimethylsulfoxide, or the like.
As a preferable scheme, the oil bath temperature can reach more than 80% of the yield of the target compound under the oil bath conditions of 100 ℃, 105 ℃ and 110 ℃, wherein the oil bath temperature is the optimal yield of the reaction at 105 ℃. As a preferred embodiment of the present invention,
preferably, the results obtained after the column chromatography separation show that: after 4 hours of reaction, the yield can reach more than 71 percent; after 10 hours of reaction, the yield of the reaction is optimal; the reaction time was continued to be prolonged, and the yield of the objective compound was not increased.
As a preferred scheme, the substituent halogen atom X in the 2-halogenated alpha, beta-unsaturated alkynone can be F, cl and Br.
As a preferred embodiment, the substituents R may be substituents Me, OMe, C with electron donating groups 3 H 5 。
(III) beneficial effects
Compared with the prior art, the invention provides a synthesis method of chromone compounds, which comprises the following steps of
The beneficial effects are that:
1. the invention solves the problem of difficult and expensive raw material alcohol purchase, and can reduce the cost of raw material alcohol purchase. This helps laboratories and researchers to save costs and allows more efficient use of research expenses; the amount of raw alcohol used can be reduced by optimizing the synthesis route and improving the synthesis efficiency. This helps to reduce reliance on limited resources, improve laboratory sustainability, and reduce environmental impact.
2. The synthesis method has better universality, saves time and resources, and does not need to develop an independent synthesis route for each compound. The 3-position thiophene ring of the chromone compound obtained by the reaction of the 2-bromoalpha, beta-unsaturated alkynone and the benzothiophene-2-methanol is successfully connected with benzene ring substituent groups to form a benzothiophene structure, and the serial synthesis method has better universality and is suitable for introducing functional groups of various substitution types to the 3-position thiophene ring of the chromone parent nucleus.
Drawings
FIG. 1 is a schematic diagram of a synthetic route of the present invention;
FIG. 2 shows the present invention 1 H-NMR spectrum of compound q schematic;
FIG. 3 shows the present invention 13 C-NMR spectrum of compound q schematic;
FIG. 4 shows the present invention 1 H-NMR spectrum of compound p schematic;
FIG. 5 shows the present invention 13 C-NMR spectrum of compound p schematic;
FIG. 6 shows the present invention 1 H-NMR spectrum of compound o schematic;
FIG. 7 shows the present invention 13 C-NMR spectrum of compound o schematic;
FIG. 8 shows the present invention 1 H-NMR spectrum of compound m schematic;
FIG. 9 shows the present invention 13 C-NMR spectrum of compound m schematic;
Detailed Description
The following describes in detail the synthesis of a 3-heterocyclic substituted chromone derivative according to the present invention with reference to the accompanying drawings and specific examples. While the invention has been described herein in terms of the preferred and preferred embodiments, the following embodiments are intended to be more illustrative, and may be implemented in many alternative ways as will occur to those of skill in the art; and the accompanying drawings are only for the purpose of describing the embodiments more specifically and are not intended to limit the invention specifically.
Example 1
The synthesis route takes alcohol as a substrate and 2-halogenated alpha, beta-unsaturated alkynone compound as a raw material, and the chromone compound is synthesized by the action of alkali, and the synthesis mode of the thiochromone compound is as follows:
taking 0.5mmol of compound 1q and 0.7mmol of furfuryl mercaptan as reaction substrates in the experimental process, adding one drop of tributylphosphine as a catalyst and a proper amount of dimethyl sulfoxide as a solvent, magnetically stirring at room temperature for reaction for 2 hours, directly adding 1mmol of double-equivalent potassium carbonate into the same reaction system, adding a nitrogen protection device, continuously pumping out air for five times to remove oxygen, placing a round-bottom flask in an oil bath pot at 105 ℃ for magnetically stirring for reaction for 10 hours, and separating yellow solid compound 3q by silica gel column chromatography, wherein the yield is 91%.
The nmr hydrogen spectrum and mass spectrum characterization data of compound 3q are as follows:
2- (4-methoxyphenyl) -4H-chrome-4-one (3 q) The compound was purified by column chromatography (silica gel, PE/EtOAc=10/1 v/v): 115mg,91% yield; yellow solid, mp 96-101 ℃ 1H NMR (400 mhz, cdcl 3) delta 8.52 (d, j=8.0 hz, 1H), 7.62 (m, 4H), 7.53 (t, j=8.0 hz, 1H), 7.20 (s, 1H), 7.00 (d, j=8.0 hz, 2H), 3.87 (s, 3H); 13C {1H } NMR (100 MHz, CDCl 3) delta 180.9,161.8,152.8,137.6,131.5,130.8,128.7,128.5,128.3,127.6,126.4,122.1,114.6,55.5.HRMS M/z (ESI) calcd for C16H12O3, (M+H) +253.0860; found,253.0865 nuclear magnetic data analysis showed: the thiochromone derivative is obtained through synthesis.
Example 2
The synthesis route takes alcohol as a substrate and 2-halogenated alpha, beta-unsaturated alkynone compound as a raw material, and the chromone compound is synthesized by the action of alkali, and the synthesis mode of the thiochromone compound is as follows:
taking 0.5mmol of compound 1q and 0.7mmol of furfuryl mercaptan as reaction substrates in the experimental process, adding one drop of tributylphosphine as a catalyst and a proper amount of dimethyl sulfoxide as a solvent, magnetically stirring at room temperature for reaction for 2 hours, directly adding 1mmol of double-equivalent potassium carbonate into the same reaction system, adding a nitrogen protection device, continuously pumping out air for five times to remove oxygen, placing a round-bottom flask in an oil bath pot at 105 ℃ for magnetically stirring for reaction for 10 hours, and separating yellow solid compound 3q by silica gel column chromatography, wherein the yield is 91%.
The synthesis mode of the 3-substituted chromone compound in the chromone compound is as follows:
taking 0.5mmol of compound 1p and 0.7mmol of allyl mercaptan as reaction substrates in the experimental process, adding one drop of tributylphosphine as a catalyst and a proper amount of dimethyl sulfoxide as a solvent, magnetically stirring at room temperature for reaction for 2 hours, directly adding 1mmol of double-equivalent potassium carbonate into the same reaction system, adding a nitrogen protection device, continuously pumping out gas for five times to remove oxygen, placing a round-bottom flask into an oil bath pot at 105 ℃ for magnetically stirring for reaction for 10 hours, and separating eluent by silica gel column chromatography: PE/EtOAc=10/1, 6/1, v/v yellow liquid, compound 3p, 92% yield.
The nmr hydrogen spectrum and mass spectrum characterization data of compound 3p are as follows:
3-allyl-2-phenyl-4H-thiochromen-4-one(3p)The compound was purified by column chromatography(silica gel,PE/EtOAc＝10/1v/v):128mg,92％yield；yellow liquid,mp.1H NMR(400MHz,CDCl3)δ8.57(d,J＝8.0Hz,1H),7.53(m,8H),5.93(m,1H),4.96(d,J＝12.0Hz,1H),4.87(d,J＝16.0Hz,1H),3.33(d,J＝4.0Hz,2H)；13C{1H}NMR(100MHz,CDCl3)δ179.6,149.6,137.5,136.4,136.0,132.7,131.2,130.4,129.4,129.2,128.5(2C),127.3,125.6,115.3,32.9.HRMS m/z(ESI)calcd for C8H14SO,(M+H)+279.0838；found,279.0835.
the invention needs to be further explained as follows: nuclear magnetic data analysis showed that: the introduction of 3-position allyl of the thiochromone compound obtained by the reaction of the 2-bromoalpha, beta-unsaturated alkynone and the furfuryl mercaptan is successful, and compared with the conventional target compound, 3p is liquid, the synthesis method has better universality, is suitable for introducing various types of functional groups into the 3-position of the chromone parent nucleus, and provides a new thought for constructing the 3-position functionalized thiochromone skeleton.
Example 3
The synthesis route takes alcohol as a substrate and 2-halogenated alpha, beta-unsaturated alkynone compound as a raw material, and the chromone compound is synthesized by the action of alkali, and the synthesis mode of the thiochromone compound is as follows:
taking 0.5mmol of compound 1q and 0.7mmol of furfuryl mercaptan as reaction substrates in the experimental process, adding one drop of tributylphosphine as a catalyst and a proper amount of dimethyl sulfoxide as a solvent, magnetically stirring at room temperature for reaction for 2 hours, directly adding 1mmol of double-equivalent potassium carbonate into the same reaction system, adding a nitrogen protection device, continuously pumping out air for five times to remove oxygen, placing a round-bottom flask in an oil bath pot at 105 ℃ for magnetically stirring for reaction for 10 hours, and separating yellow solid compound 3q by silica gel column chromatography, wherein the yield is 91%.
The synthesis mode of the chromone compound 3o is as follows:
taking 0.5mmol of compound 1o and 0.7mmol of allyl alcohol as reaction substrates in the experimental process, adding one drop of tributylphosphine as a catalyst and a proper amount of dimethyl sulfoxide as a solvent, magnetically stirring and reacting for 2 hours at room temperature, directly adding 1mmol of double-equivalent potassium carbonate into the same reaction system, adding a nitrogen protection device, continuously pumping out and discharging gas for five times to remove oxygen, placing a round-bottom flask into an oil bath pot at 105 ℃ for magnetically stirring and reacting for 10 hours, separating by silica gel column chromatography, and eluting with an eluent: PE/EtOAc=10/1, 6/1, v/v yellow solid, compound 3o, 89% yield.
The nmr hydrogen spectrum and mass spectrum characterization data for compound 3o are as follows:
3-allyl-2-phenyl-4H-chromen-4-one(3o)The compound was purified by column chromatography(silicagel,PE/EtOAc＝10/1v/v):117mg,89％yield；yellow solid,mp 86–91℃.1H NMR(400MHz,CDCl3)δ8.57(d,J＝8.0Hz,1H),7.53(m,8H),5.93(m,1H),4.96(d,J＝12.0Hz,1H),4.87(d,J＝16.0Hz,1H),3.33(d,J＝4.0Hz,2H)；13C{1H}NMR(100MHz,CDCl3)δ179.6,149.6,137.5,136.4,136.0,132.7,131.2,130.4,129.4,129.2,128.5(2C),127.3,125.6,115.3,32.9.HRMS m/z(ESI)calcd for C18H14O2,(M+H)+263.1067；found,263.1067.
the invention needs to be explained by nuclear magnetic data analysis to show that: the introduction of the 3-position allyl of the chromone compound obtained by the reaction of the 2-bromoalpha, beta-unsaturated acetylenic ketone and furfuryl alcohol is successful, and compared with the 3p of the target compound, the 3o is solid, and the one-pot serial synthesis method has better universality and is suitable for introducing various functional groups into the 3-position of the chromone parent nucleus.
Example 4
The synthesis route takes alcohol as a substrate and 2-halogenated alpha, beta-unsaturated alkynone compound as a raw material, and the chromone compound is synthesized by the action of alkali, and the synthesis mode of the thiochromone compound is as follows:
taking 0.5mmol of compound 1q and 0.7mmol of furfuryl mercaptan as reaction substrates in the experimental process, adding one drop of tributylphosphine as a catalyst and a proper amount of dimethyl sulfoxide as a solvent, magnetically stirring at room temperature for reaction for 2 hours, directly adding 1mmol of double-equivalent potassium carbonate into the same reaction system, adding a nitrogen protection device, continuously pumping out air for five times to remove oxygen, placing a round-bottom flask in an oil bath pot at 105 ℃ for magnetically stirring for reaction for 10 hours, and separating yellow solid compound 3q by silica gel column chromatography, wherein the yield is 91%. The synthesis of the chromone compound comprises the 3-thiophene chromone compound, and the reaction mode is as follows:
2-acetylthiophene (5 mmol), 10 times sodium borohydride (25 mmol) and methanol as solvent are added into a 100ml round bottom flask, and the corresponding alcohol can be produced by magnetic stirring reaction for 3h under ice bath condition because the oxidation-reduction reaction is relatively severe. After the reaction was completed, the solvent methanol was removed by concentrating under reduced pressure, the filtrate was repeatedly extracted 3 times with ethyl acetate and water, and the upper ethyl acetate layer was collected for thin layer chromatography TLC, and spots of different heights appeared on TLC by the difference in polarity of the compounds. Observing that the obtained raw material alcohol is a compound with relatively large polarity in a dark box type ultraviolet analyzer, concentrating the filtrate collected after extraction again under reduced pressure, removing ethyl acetate, separating residues by column chromatography to remove insoluble substances such as salts generated in the reaction process, and finally obtaining a compound (S/R) -1- (2-thiophene) ethanol, and eluting with an eluent: PE/EtOAc=3/1, 1/1, v/v to give a pale yellow liquid with 97% yield of the compound; then 0.5mmol of compound 1 and 0.7mmol of (S/R) -1- (2-thiophene) ethanol are taken as reaction substrates in the experimental process, one drop of tributylphosphine is taken as a catalyst, a proper amount of dimethyl sulfoxide is taken as a solvent, after magnetically stirring and reacting for 2 hours at room temperature, 1mmol of twice equivalent potassium carbonate is directly added into the same reaction system, a nitrogen protection device is added, and continuously pumping out air for five times to remove oxygen, after the round bottom flask is placed in an oil bath pot at 105 ℃ for magnetically stirring and reacting for 10 hours, silica gel column chromatography separation is carried out, and eluent: PE/EtOAc=10/1, 6/1, v/v, yellow solid, compound 3m, 92% yield.
The nmr hydrogen spectrum and mass spectrum characterization data for compound 3m are as follows:
3-(2-ethylthiophen-3-yl)-2-phenyl-4H-chromen-4-one(3m)Thecompound was purified by column chromatography(silica gel,PE/EtOAc＝10/1v/v):153mg,92％yield；yellow solid,mp 109–114℃.1H NMR(400MHz,CDCl3)δ8.28(d,J＝8.0Hz,1H),7.71(t,J＝8.0Hz,1H),7.55(d,J＝8.0Hz,1H),7.36(m,6H),7.16(d,J＝4.0Hz,1H),6.86(d,J＝4.0Hz,1H),2.53(m,1H),2.26(m,1H)0.97(t,J＝8.0Hz,3H)；13C{1H}NMR(100MHz,CDCl3)δ177.5,161.6,156.0,145.0,133.7,133.3,130.2,129.8,128.8,128.1,128.0,126.3,125.1,123.2,122.1,117.9,117.8,21.9,15.2.HRMS m/z(ESI)calcd for C21H16SO2,(M+H)+333.0944；found,333.0947.
the invention needs to be further explained as follows: nuclear magnetic data analysis showed that: the ethyl substituent group is successfully connected to the 3-position thiophene ring of the chromone compound obtained by reacting 2-bromoalpha, beta-unsaturated acetylenic ketone with (S/R) -1- (2-thiophene) ethanol, the one-pot serial synthesis method has better universality, is suitable for introducing functional groups of various substitution types into the 3-position furan ring and thiophene ring of the chromone parent nucleus (ethyl is introduced into the 3m thiophene ring of the compound, benzene ring is introduced into the 3n thiophene ring of the compound, benzene ring is introduced into the 3e furan ring of the compound, and methyl is introduced into the 3d furan ring of the compound), provides a new idea for constructing a 3-position functionalized chromone skeleton, and simultaneously, can find a simple synthesis method for alcohol compounds which are difficult to obtain by a chemical method.
Example 5
The synthesis route takes alcohol as a substrate and 2-halogenated alpha, beta-unsaturated alkynone compound as a raw material, and the chromone compound is synthesized by the action of alkali, and the synthesis mode of the thiochromone compound is as follows:
taking 0.5mmol of compound 1q and 0.7mmol of furfuryl mercaptan as reaction substrates in the experimental process, adding one drop of tributylphosphine as a catalyst and a proper amount of dimethyl sulfoxide as a solvent, magnetically stirring at room temperature for reaction for 2 hours, directly adding 1mmol of double-equivalent potassium carbonate into the same reaction system, adding a nitrogen protection device, continuously pumping out air for five times to remove oxygen, placing a round-bottom flask in an oil bath pot at 105 ℃ for magnetically stirring for reaction for 10 hours, and separating yellow solid compound 3q by silica gel column chromatography, wherein the yield is 91%.
The solvent is selected from N, N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, etc.
The oil bath temperature can reach more than 80% of the yield of the target compound under the conditions of 100 ℃, 105 ℃ and 110 ℃ oil bath, wherein the oil bath temperature is the optimal yield of the reaction at 105 ℃.
The results obtained after separation by column chromatography showed that: after 4 hours of reaction, the yield can reach more than 71 percent; after 10 hours of reaction, the yield of the reaction is optimal; the reaction time was continued to be prolonged, and the yield of the objective compound was not increased.
The substituent halogen atom X in the 2-halogenated alpha, beta-unsaturated alkynone can be F, cl and Br.
The substituent R may be a substituent Me, OMe, C with an electron donating group 3 H 5 。

Claims (9)

1. A synthesis method of chromone compounds is characterized in that: the synthesis route takes alcohol as a substrate and 2-halogenated alpha, beta-unsaturated alkynone compound as a raw material, and the chromone compound is synthesized by the action of alkali, and the synthesis mode of the thiochromone compound is as follows:
taking 0.5mmol of compound 1q and 0.7mmol of furfuryl mercaptan as reaction substrates in the experimental process, adding one drop of tributylphosphine as a catalyst and a proper amount of dimethyl sulfoxide as a solvent, magnetically stirring at room temperature for reaction for 2 hours, directly adding 1mmol of double-equivalent potassium carbonate into the same reaction system, adding a nitrogen protection device, continuously pumping out air for five times to remove oxygen, placing a round-bottom flask in an oil bath pot at 105 ℃ for magnetically stirring for reaction for 10 hours, and separating yellow solid compound 3q by silica gel column chromatography, wherein the yield is 91%.
2. The method for synthesizing chromone compounds according to claim 1, wherein: the synthesis mode of the 3-substituted chromone compound in the chromone compound is as follows:
taking 0.5mmol of compound 1p and 0.7mmol of allyl mercaptan as reaction substrates in the experimental process, adding one drop of tributylphosphine as a catalyst and a proper amount of dimethyl sulfoxide as a solvent, magnetically stirring at room temperature for reaction for 2 hours, directly adding 1mmol of double-equivalent potassium carbonate into the same reaction system, adding a nitrogen protection device, continuously pumping out gas for five times to remove oxygen, placing a round-bottom flask into an oil bath pot at 105 ℃ for magnetically stirring for reaction for 10 hours, and separating eluent by silica gel column chromatography: PE/EtOAc=10/1, 6/1, v/v yellow liquid, compound 3p, 92% yield.
3. The method for synthesizing chromone compounds according to claim 1, wherein: the synthesis mode of the chromone compound 3o is as follows:
taking 0.5mmol of compound 1o and 0.7mmol of allyl alcohol as reaction substrates in the experimental process, adding one drop of tributylphosphine as a catalyst and a proper amount of dimethyl sulfoxide as a solvent, magnetically stirring and reacting for 2 hours at room temperature, directly adding 1mmol of double-equivalent potassium carbonate into the same reaction system, adding a nitrogen protection device, continuously pumping out and discharging gas for five times to remove oxygen, placing a round-bottom flask into an oil bath pot at 105 ℃ for magnetically stirring and reacting for 10 hours, separating by silica gel column chromatography, and eluting with an eluent: PE/EtOAc=10/1, 6/1, v/v yellow solid, compound 3o, 89% yield.
4. The method for synthesizing chromone compounds according to claim 1, wherein: the synthesis of the chromone compound comprises a 3-thiophene chromone compound, and the reaction mode is as follows:
2-acetylthiophene (5 mmol), 10 times sodium borohydride (25 mmol) and methanol as solvent are added into a 100ml round bottom flask, and the corresponding alcohol can be generated by magnetic stirring reaction for 3h under ice bath condition because the oxidation-reduction reaction is more severe; after the reaction is finished, removing the solvent methanol after decompression concentration, repeatedly extracting the filtrate with ethyl acetate and water for 3 times, collecting the upper ethyl acetate layer spot-size plate thin-layer chromatography TLC, and generating spots with different heights on the TLC through the difference of the polarities of the compounds; observing that the obtained raw material alcohol is a compound with relatively large polarity in a dark box type ultraviolet analyzer, concentrating the filtrate collected after extraction again under reduced pressure, removing ethyl acetate, separating residues by column chromatography to remove insoluble substances such as salts generated in the reaction process, and finally obtaining a compound (S/R) -1- (2-thiophene) ethanol, and eluting with an eluent: PE/EtOAc=3/1, 1/1, v/v to give a pale yellow liquid with 97% yield of the compound; then 0.5mmol of compound 1 and 0.7mmol of (S/R) -1- (2-thiophene) ethanol are taken as reaction substrates in the experimental process, one drop of tributylphosphine is taken as a catalyst, a proper amount of dimethyl sulfoxide is taken as a solvent, after magnetically stirring and reacting for 2 hours at room temperature, 1mmol of twice equivalent potassium carbonate is directly added into the same reaction system, a nitrogen protection device is added, and continuously pumping out air for five times to remove oxygen, after the round bottom flask is placed in an oil bath pot at 105 ℃ for magnetically stirring and reacting for 10 hours, silica gel column chromatography separation is carried out, and eluent: PE/EtOAc=10/1, 6/1, v/v, yellow solid, compound 3m, 92% yield.
5. The method for synthesizing chromone compounds according to claim 1, wherein: the selected solvent comprises N, N-dimethylformamide, N-methylpyrrolidone and dimethyl sulfoxide.
6. The method for synthesizing chromone compounds according to claim 1, wherein: the oil bath pot temperature reaches more than 80% of the yield of the target compound under the oil bath conditions of 100 ℃, 105 ℃ and 110 ℃, wherein the oil bath temperature is 92% of the yield of the reaction at 105 ℃.
7. The method for synthesizing chromone compounds according to claim 1, wherein: the results obtained after the column chromatography separation showed that: after 4 hours of reaction, the yield reaches more than 71%; after 10 hours of reaction, the yield of the reaction reaches 90 percent; the reaction time was continued to be prolonged, and the yield of the objective compound was not increased.
8. The method for synthesizing chromone compounds according to claim 1, wherein: the substituent halogen atom X in the 2-halogenated alpha, beta-unsaturated alkynone comprises F, cl and Br.
9. The method for synthesizing chromone compounds according to claim 1, wherein: substituents R, including substituents Me, OMe, C with electron donating groups 3 H 5 。
CN202311061080.7A 2023-08-23 2023-08-23 Synthesis method of chromone compound Pending CN117088846A (en)

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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104262309A (en) * 2014-09-11 2015-01-07 华东师范大学 Chromone derivative and synthesis method thereof

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104262309A (en) * 2014-09-11 2015-01-07 华东师范大学 Chromone derivative and synthesis method thereof

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
XUESONG WANG等: ""Tandem synthesis of 3-allyl-chromones from alkynones and allylic alcohols under metal-free conditions"", 《COMMUNICATION》, vol. 50, 5 November 2013 (2013-11-05), pages 652 - 654 *

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