CN112939917B - Preparation method of flavonoid compound - Google Patents
Preparation method of flavonoid compound Download PDFInfo
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- CN112939917B CN112939917B CN202110180984.6A CN202110180984A CN112939917B CN 112939917 B CN112939917 B CN 112939917B CN 202110180984 A CN202110180984 A CN 202110180984A CN 112939917 B CN112939917 B CN 112939917B
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- 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
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- 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
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Abstract
The invention belongs to the technical field of organic synthesis, and discloses a preparation method of flavonoid compounds. The invention provides a preparation method of a flavonoid compound, which comprises the steps of taking oxo-isatin or oxo-isatin substituted on a benzene ring, taking phenylacetylene or substituted phenylacetylene as a reaction substrate, taking a nickel catalyst and a ligand as a catalyst, taking inorganic base as a cocatalyst, and carrying out cyclization reaction after removing carbon monoxide through nickel catalysis in a solvent environment to obtain the flavonoid compound. The method has the advantages of simple reaction process operation and low cost, and strong acid, strong alkali, strong corrosiveness and toxic reagents are not needed; high reaction efficiency, high yield, less byproducts, no need of noble metals and expensive ligands. Meanwhile, the substituent effect of the raw materials has little influence on the reaction, and can synthesize various substituted and various structural compounds containing the flavone skeleton, thereby greatly expanding the types of the flavone compounds.
Description
Technical Field
The invention belongs to the technical field of organic synthesis, and particularly relates to a preparation method of a flavonoid compound.
Background
Flavonoid compounds are widely present in nature and living bodies, have wide biological and pharmacological activities including oxidation resistance, anticancer activity, anti-inflammatory activity, and the like, and thus are also widely used in pharmaceuticals and nutritional agents ((a) chem.rev.2014,114, 4960-4992), (b) eur.j.med.chem.2014,84,206-239, (c) j.med.chem.1990,33,3210-3216, (d) j.med.chem.1990,33,3216-3222, (e) j.med.chem.1992,35,3519-3525, (f) j.med.chem.2011,54,7427-7431, (g) eur.j.med.chem.2015,90,251-257. The establishment of efficient synthesis methods of the molecules is always one of the research directions which are paid attention to in the field of organic synthesis.
The traditional method for constructing flavonoid compound parent nucleus is to take o-acyl phenol compound as substrate, add anhydride and carboxylate and acylate and cyclize at high temperature to obtain the product ((a) J.chem.Soc., trans.1924,125,2192-2195, (b) J.org.chem.1961,26,2453-2455, and (c) J.org.chem.1978,43, 2344-2347). The method is complex, the toxicity and corrosiveness of reagent anhydride are strong, the reaction temperature is high, the O-acyl phenol compound is prepared by a certain step, strong acid and high temperature conditions are needed in the preparation process, the tolerance of functional groups is poor, the total yield of the synthetic route is low, and the method does not meet the requirements of green chemistry.
To ameliorate the shortcomings and limitations of traditional synthetic methods, several alternatives have been developed. For example, a method of palladium-catalyzed cyclization in a CO atmosphere using o-iodophenol and phenylacetylene as starting materials ((a) Tetrahedron letters 1990,31,4073-4076, (b) Tetrahedron 1991,47,6449-6456, (c) Tetrahedron 1993,49,6773-6784, (d) org.letters 2000,2,1765-1768, (e) org.letters 2009,11,3210-3213, (f) J.org.chem.2010,75, 948-950); palladium-catalyzed 2-hydrogen activation method using chromone and arylboronic acid as raw materials ((a) chem.Commun.2012,48,2985-2987, (b) org.biomol.chem.2012,10,7305-7312, (c) Tetrahedron lett.2012,53,2761-2764, (d) angel.chem.int.ed.2012, 51,11333-11336, (e) org.biomol.chem.2016,14, 777-784.); the method takes salicylaldehyde and phenylacetylene as raw materials, rhodium, ruthenium and cobalt are used for catalyzing cyclization ((a) chem. Asian J.2008,3,881-886, (b) Angew. Chem. Int. Ed.2016,55,2870-2874, (c) chem. Commun.2016,52,13004-13007, (d) org. Lett.2017,19,6606-6609. The methods adopt metal catalysis, and can simplify the synthetic route, but noble metals, complex and expensive ligands, toxic reagents, high pressure and other severe reaction conditions are often required, and the synthetic yield is difficult to ensure.
Reaction equation 1
In view of the above, development of a novel efficient, low-cost, green synthetic method for flavonoids is still urgent and necessary.
Disclosure of Invention
In order to overcome the defects and shortcomings of the prior art, the primary purpose of the invention is to provide a preparation method of flavonoid compounds, which has low cost, high efficiency, avoidance of toxic and harmful substances and simple operation.
The aim of the invention is achieved by the following scheme:
a process for preparing flavonoid compounds includes such steps as preparing the substrate of substituted oxo-isatin on benzene ring, phenylacetylene or substituted phenylacetylene, ni catalyst and ligand, inorganic alkali as promoter, and cyclizing reaction in solvent to remove CO by Ni catalyst.
The reaction equation of the preparation method is shown as the following formula (II):
two kinds of
In the preparation method of the invention, the benzene ring is substitutedAfter oxo-isatin, one or more hydrogen-containing groups (R 2 ) The substitution, the groups being identical or different, may be selected from halogen atoms, trifluoromethyl groups, alkyl groups having 1 to 10 carbon atoms, cycloalkyl groups having 3 to 10 carbon atoms, alkoxy groups having 1 to 10 carbon atoms, carboxyl groups, -COOR groups, -CONH groups 2 or-CONHR or-CONRR', -NH 2 or-NHR or-NRR', an aryl group having 6 to 20 carbon atoms, and the above groups having one or more secondary substituents.
The secondary substituents, which may be the same or different, may be selected from the group consisting of an aryl group having 6 to 20 carbon atoms, an alkyl group having 1 to 10 carbon atoms, an alkoxy group having 1 to 10 carbon atoms, a trifluoromethyl group, and a halogen atom, respectively.
R and R' are the same or different and can be selected from aryl groups with 6-20 carbon atoms, alkyl groups with 1-10 carbon atoms, trifluoromethyl and halogen atoms respectively.
In the preparation method of the invention, one or more hydrogen-convertible groups (R) on the aromatic ring Ar of the substituted phenylacetylene 1 ) The substitution, the groups are the same or different and can be selected from halogen atom, trifluoromethyl, alkyl with 1-10 carbon atoms, cycloalkyl with 3-10 carbon atoms, alkoxy with 1-10 carbon atoms, carboxyl, trialkylsilyl with 1-5 carbon atoms, trialkylsiloxy with 1-5 carbon atoms, -CN, -OCOR, -COR, -COOR and-CONH 2 or-CONHR or-CONRR', -NH 2 or-NHR or-NRR', an aryl group having 6 to 20 carbon atoms, and the above groups having one or more secondary substituents.
The secondary substituents, which may be the same or different, may be selected from the group consisting of an aryl group having 6 to 20 carbon atoms, an alkyl group having 1 to 10 carbon atoms, an alkoxy group having 1 to 10 carbon atoms, a trifluoromethyl group, and a halogen atom, respectively.
R and R' are the same or different and can be selected from aryl with 6-20 carbon atoms, alkyl with 1-10 carbon atoms, trifluoromethyl and halogen atoms, -COOR. R' may be selected from alkyl groups having 1 to 10 carbon atoms.
The aromatic ring Ar is an aromatic group with different connection positions and can be selected from phenyl, naphthyl, furyl, pyrrolyl, thienyl, pyridyl and a group condensed by one or more than one groups.
In the preparation method of the invention, the hydrogen on the ethynyl of the substituted phenylacetylene can be substituted by a group (R 3 ) The groups are the same or different and can be selected from alkyl with 1-10 carbon atoms, carboxyl with 1-10 carbon atoms, -COR, -COOR and CONH 2 or-CONHR or-CONRR', -NH 2 or-NHR or-NRR', and those in which one or more hydrogens are replaced with a secondary substituent.
The secondary substituents, which may be the same or different, may be selected from the group consisting of an aryl group having 6 to 20 carbon atoms, an alkyl group having 1 to 10 carbon atoms, an alkoxy group having 1 to 10 carbon atoms, a trifluoromethyl group, and a halogen atom, respectively.
R and R' are the same or different and can be selected from aryl groups with 6-20 carbon atoms, alkyl groups with 1-10 carbon atoms, trifluoromethyl and halogen atoms respectively.
In the preparation method of the invention, the molar ratio of the used oxo-indigo red or the oxo-indigo red substituted on the benzene ring to phenylacetylene or the substituted phenylacetylene is preferably 1:1.2-1:2.
The nickel catalyst is preferably used in an amount of 5 to 10mol% based on the amount of oxo-indigo red or oxo-indigo red substituted on the benzene ring.
The amount of the ligand is preferably 5 to 10mol% of the amount of the oxo-indigo red substituted on the oxo-indigo red or the benzene ring.
The amount of the inorganic base is 0 to 2 equivalents, preferably 1 equivalent, of the amount of the oxo-indigo red or the oxo-indigo red substance substituted on the benzene ring.
The nickel-catalyzed reaction may be carried out at room temperature-180 ℃, preferably at 60-140 ℃, more preferably at 120 ℃.
The nickel catalyst may be selected from bis (1, 5-cyclooctadiene) nickel, nickel chloride, nickel acetate, nickel perchlorate, and the like.
The ligand may be selected from triphenylphosphine, tricyclohexylphosphine, 1, 3-bis (diphenylphosphine) ethane, 1, 3-bis (diphenylphosphine) propane, 1, 3-bis (diphenylphosphine) butane, 1' -bis (diphenylphosphine) ferrocene, 1' -binaphthyl-2, 2' -bisdiphenylphosphine, or the above ligands in which one or more hydrogens on the aromatic ring or alkyl chain are substituted with substituents.
The substituent comprises hydroxy, carboxyl, -COOR, -CONH 2 or-CONHR or-CONRR', -NH 2 or-NHR or-NRR', alkyl having 1 to 10 carbon atoms, alkoxy having 1 to 10 carbon atoms, aryl having 6 to 20 carbon atoms, aryloxy having 6 to 20 carbon atoms, and the above groups in which one or more hydrogens are replaced with a secondary substituent.
R and R' are the same or different and can be selected from alkyl groups with 1-10 carbon atoms respectively.
The secondary substituents, which may be the same or different, may be selected from halogen groups, carboxyl groups, hydroxyl groups, amino groups, trifluoromethyl groups, trimethylsilyl groups, triethylsilyl groups, tributylsilyl groups, trimethylsiloxy groups, triethylsiloxy groups, tributylsiloxy groups, or azido groups, respectively.
In the inorganic base, the cation can be alkali metal ion, alkaline earth metal ion, ammonium ion, and the anion can be carbonate ion, bicarbonate ion, phosphate ion, HPO 4 - Fluoride ion, carboxylate ion with 1-10 carbon atoms, and alkoxy anion with 1-10 carbon atoms.
The solvent can be toluene, benzene, xylene, mesitylene, chlorobenzene, nitrobenzene, benzotrifluoride, tetrahydrofuran, ethylene glycol dimethyl ether, methyl tertiary butyl ether, dimethyl sulfoxide, N-dimethylformamide, N-dimethylacetamide, pyrrolidone, N-methylpyrrolidone and acetonitrile or a mixture of more than one of the above; preferably at least one of toluene, xylene, mesitylene, chlorobenzene, nitrobenzene.
The structural formula of the flavonoid compound prepared by the method is shown as follows:
flavonoid compounds of the inventionIn the compound, substituent R 1 Is selected from halogen atom, trifluoromethyl, C1-10 alkyl, C3-10 cycloalkyl, C1-10 alkoxy, carboxyl, C1-5 trialkylsilyl, C1-5 trialkylsiloxy, -CN, -OCOR, -COR, -COOR, -CONH 2 or-CONHR or-CONRR', -NH 2 or-NHR or-NRR', an aryl group having 6 to 20 carbon atoms, and the above groups having one or more secondary substituents.
The secondary substituents, which may be the same or different, may be selected from the group consisting of an aryl group having 6 to 20 carbon atoms, an alkyl group having 1 to 10 carbon atoms, an alkoxy group having 1 to 10 carbon atoms, a trifluoromethyl group, and a halogen atom, respectively.
R and R' are the same or different and can be selected from aryl with 6-20 carbon atoms, alkyl with 1-10 carbon atoms, trifluoromethyl and halogen atoms, -COOR. R' may be selected from alkyl groups having 1 to 10 carbon atoms.
The aromatic ring Ar is an aromatic group with different connection positions and can be selected from phenyl, naphthyl, furyl, pyrrolyl, thienyl, pyridyl and a group condensed by one or more than one groups.
In the flavonoid compound of the invention, the substituent R 3 Can be selected from alkyl with 1-10 carbon atoms, carboxyl with 1-10 carbon atoms, -COR, -COOR, -CONH 2 or-CONHR or-CONRR', -NH 2 or-NHR or-NRR', and those in which one or more hydrogens are replaced with a secondary substituent.
The secondary substituents, which may be the same or different, may be selected from the group consisting of an aryl group having 6 to 20 carbon atoms, an alkyl group having 1 to 10 carbon atoms, an alkoxy group having 1 to 10 carbon atoms, a trifluoromethyl group, and a halogen atom, respectively.
R and R' are the same or different and can be selected from aryl groups with 6-20 carbon atoms, alkyl groups with 1-10 carbon atoms, trifluoromethyl and halogen atoms respectively.
In the flavonoid compound of the invention, the substituent R 2 Selected from halogen atoms, trifluoromethyl groups, and C1-10, cycloalkyl having 3 to 10 carbon atoms, alkoxy having 1 to 10 carbon atoms, carboxyl, -COOR, -CONH 2 or-CONHR or-CONRR', -NH 2 or-NHR or-NRR', an aryl group having 6 to 20 carbon atoms, and the above groups having one or more secondary substituents.
The secondary substituents, which may be the same or different, may be selected from the group consisting of an aryl group having 6 to 20 carbon atoms, an alkyl group having 1 to 10 carbon atoms, an alkoxy group having 1 to 10 carbon atoms, a trifluoromethyl group, and a halogen atom, respectively.
R and R' are the same or different and can be selected from aryl groups with 6-20 carbon atoms, alkyl groups with 1-10 carbon atoms, trifluoromethyl and halogen atoms respectively.
Compared with the prior art, the invention has the following advantages:
(1) The method has the advantages of simple reaction process operation and low cost, and strong acid, strong alkali, strong corrosiveness and toxic reagents are not needed; high reaction efficiency, high yield, less byproducts, no need of noble metals and expensive ligands.
(2) In the method, the substituent effect of the raw materials has little influence on the reaction, and can synthesize various substituted and various structural compounds containing the flavone skeleton, thereby greatly expanding the types of the flavone compounds and having wide applicability.
Detailed Description
The present invention will be described in further detail with reference to examples, but embodiments of the present invention are not limited thereto. The materials referred to in the examples below are available commercially unless otherwise specified. The method is conventional unless otherwise specified.
In one embodiment, the preparation method of the flavonoid compound is characterized in that oxo-isatin or oxo-isatin substituted on a benzene ring is used as a reaction substrate with phenylacetylene or substituted phenylacetylene, a nickel catalyst and a ligand are used as a catalyst, an inorganic base is used as a cocatalyst, and the flavonoid compound is obtained through a cyclization reaction after carbon monoxide is removed by nickel catalysis in a solvent environment.
In the preparation method of the invention, the benzene ring is substitutedAfter oxo-isatin, one or more hydrogen-containing groups (R 2 ) The substitution, the groups being identical or different, may be selected from halogen atoms, trifluoromethyl groups, alkyl groups having 1 to 10 carbon atoms, cycloalkyl groups having 3 to 10 carbon atoms, alkoxy groups having 1 to 10 carbon atoms, carboxyl groups, -COOR groups, -CONH groups 2 or-CONHR or-CONRR', -NH 2 or-NHR or-NRR', an aryl group having 6 to 20 carbon atoms, and the above groups having one or more secondary substituents.
The secondary substituent may be selected from the group consisting of an aryl group having 6 to 20 carbon atoms, an alkyl group having 1 to 10 carbon atoms, an alkoxy group having 1 to 10 carbon atoms, a trifluoromethyl group, and a halogen atom.
R and R' are the same or different and can be selected from aryl groups with 6-20 carbon atoms, alkyl groups with 1-10 carbon atoms, trifluoromethyl and halogen atoms respectively.
The preparation method of the invention adopts oxo-isatin as a raw material, and the oxo-isatin and phenylacetylene are directly reacted under the catalysis of a high-efficiency catalyst to obtain the flavonoid compound. The substituents on the phenyl ring of the oxo-isatin do not generally affect the performance of the preparation process of the present invention.
For example, in one embodiment, R is 2 Is methyl; in a further embodiment, said R 2 Is a chlorine atom; in a further embodiment, said R 2 4, 6-dimethyl; the preparation method can be rapidly carried out, and the obtained yield has certain change but does not influence the reaction; thus, for R, to one of ordinary skill in the art, without departing from the inventive concept 2 Several modifications are made, which fall within the scope of the present invention.
In the preparation method of the invention, one or more hydrogen-convertible groups (R) on the aromatic ring Ar of the substituted phenylacetylene 1 ) The substitution, the groups are the same or different and can be selected from halogen atom, trifluoromethyl, alkyl with 1-10 carbon atoms, cycloalkyl with 3-10 carbon atoms, alkoxy with 1-10 carbon atoms, carboxyl, trialkylsilyl with 1-5 carbon atoms and trialkylsiloxy with 1-5 carbon atoms、-CN、-OCOR、-COR、-COOR、-CONH 2 or-CONHR or-CONRR', -NH 2 or-NHR or-NRR', an aryl group having 6 to 20 carbon atoms, and the above groups having one or more secondary substituents.
The secondary substituent may be selected from the group consisting of an aryl group having 6 to 20 carbon atoms, an alkyl group having 1 to 10 carbon atoms, an alkoxy group having 1 to 10 carbon atoms, a trifluoromethyl group, and a halogen atom.
R and R' are the same or different and can be selected from aryl with 6-20 carbon atoms, alkyl with 1-10 carbon atoms, trifluoromethyl and halogen atoms, -COOR. R' may be selected from alkyl groups having 1 to 10 carbon atoms.
The aromatic ring Ar is an aromatic group with different connection positions and can be selected from phenyl, naphthyl, furyl, pyrrolyl, thienyl, pyridyl and a group condensed by one or more than one groups.
In the preparation method of the invention, the hydrogen on the ethynyl of the substituted phenylacetylene can be substituted by a group (R 3 ) The groups are the same or different and can be selected from alkyl with 1-10 carbon atoms, carboxyl with 1-10 carbon atoms, -COR, -COOR and CONH 2 or-CONHR or-CONRR', -NH 2 or-NHR or-NRR', and those in which one or more hydrogens are replaced with a secondary substituent.
The secondary substituent may be selected from the group consisting of an aryl group having 6 to 20 carbon atoms, an alkyl group having 1 to 10 carbon atoms, an alkoxy group having 1 to 10 carbon atoms, a trifluoromethyl group, and a halogen atom.
R and R' are the same or different and can be selected from aryl groups with 6-20 carbon atoms, alkyl groups with 1-10 carbon atoms, trifluoromethyl and halogen atoms respectively.
The preparation method of the invention adopts oxo-isatin as a raw material, and the oxo-isatin and phenylacetylene are directly reacted under the catalysis of a high-efficiency catalyst to obtain the flavonoid compound. The substituents on phenylacetylene do not generally affect the performance of the preparation process of the present invention.
In one embodiment, for example, theR 1 Is n-butyl, R 3 Is hydrogen; in a further embodiment, said R 1 And R is 3 Are all hydrogen; in a further embodiment, said R 1 Is fluorine, R 3 Is hydrogen; the preparation method can be carried out rapidly, and the obtained yield has certain change but does not influence the reaction; thus, for R, to one of ordinary skill in the art, without departing from the inventive concept 1 And R is 3 Several modifications are made, which fall within the scope of the present invention.
In the preparation method of the invention, the molar ratio of the used oxo-indigo red or the oxo-indigo red substituted on the benzene ring to phenylacetylene or the substituted phenylacetylene is preferably 1:1.2-1:2.
The nickel catalyst is preferably used in an amount of 5 to 10mol% based on the amount of oxo-indigo red or oxo-indigo red substituted on the benzene ring.
The amount of the ligand is preferably 5 to 10mol% of the amount of the oxo-indigo red substituted on the oxo-indigo red or the benzene ring.
The amount of the inorganic base is 0 to 2 equivalents, preferably 1 equivalent, of the amount of the oxo-indigo red or the oxo-indigo red substance substituted on the benzene ring.
The nickel-catalyzed reaction may be carried out at room temperature-180 ℃, preferably at 60-140 ℃, more preferably at 120 ℃.
The nickel catalyst may be selected from bis (1, 5-cyclooctadiene) nickel, nickel chloride, nickel acetate, nickel perchlorate, and the like.
The ligand may be selected from triphenylphosphine, tricyclohexylphosphine, 1, 3-bis (diphenylphosphine) ethane, 1, 3-bis (diphenylphosphine) propane, 1, 3-bis (diphenylphosphine) butane, 1' -bis (diphenylphosphine) ferrocene, 1' -binaphthyl-2, 2' -bisdiphenylphosphine, or the above ligands in which one or more hydrogens on the aromatic ring or alkyl chain are substituted with substituents.
The substituent comprises hydroxy, carboxyl, -COOR, -CONH 2 or-CONHR or-CONRR', -NH 2 or-NHR or-NRR', alkyl having 1 to 10 carbon atoms, alkoxy having 1 to 10 carbon atoms, aryl having 6 to 20 carbon atoms, aryloxy having 6 to 20 carbon atoms, and one or moreThe above groups each of which is substituted with a secondary substituent.
R and R' are the same or different and can be selected from alkyl groups with 1-10 carbon atoms respectively.
The secondary substituents may be selected from halogen groups, carboxyl groups, hydroxyl groups, amino groups, trifluoromethyl groups, trimethylsilyl groups, triethylsilyl groups, tributylsilyl groups, trimethylsiloxy groups, triethylsiloxy groups, tributylsiloxy groups or azido groups.
In the inorganic base, the cation can be alkali metal ion, alkaline earth metal ion and ammonium ion, and the anion can be carbonate ion, bicarbonate ion, phosphate ion, dihydrogen phosphate ion, fluoride ion, carboxylate ion with 1-10 carbon atoms and alkoxy anion with 1-10 carbon atoms.
The solvent can be toluene, benzene, xylene, mesitylene, chlorobenzene, nitrobenzene, benzotrifluoride, tetrahydrofuran, ethylene glycol dimethyl ether, methyl tertiary butyl ether, dimethyl sulfoxide, N-dimethylformamide, N-dimethylacetamide, pyrrolidone, N-methylpyrrolidone and acetonitrile or a mixture of more than one of the above; preferably at least one of toluene, xylene, mesitylene, chlorobenzene, nitrobenzene.
The structural formula of the flavonoid compound prepared by the method is shown as follows:
detailed description of the preferred embodiments
Example 1:
the synthesis of 5, 7-dimethylflavone has the following structural formula:
4, 6-Dimethylbenzofuran-2, 3-dione (0.2 mmol), phenylacetylene (0.3 mmol), 1, 3-bis (diphenylphosphine) ethane (0.01 mmol) were charged into the reaction flask under nitrogen protection,bis (1, 5-cyclooctadiene) nickel (0.01 mmol), potassium acetate (0.2 mmol) was dissolved in toluene (2 mL). The reaction is completed after 12 hours of normal pressure reaction at 120 ℃. Removing the reaction solvent, and separating and purifying by column chromatography to obtain the target product 5, 7-dimethylflavone: white solid, 47.6mg, yield 95%. 1 H NMR(400MHz,CDCl 3 )δ7.91–7.82(m,2H),7.54–7.44(m,3H),7.16(s,1H),6.92(s,1H),6.67(s,1H),2.83(s,3H),2.41(s,3H)； 13 C NMR(101MHz,CDCl 3 )δ180.4,161.3,157.8,143.7,140.5,131.8,131.2,129.1,128.9,126.0,120.0,115.9,108.7,22.6,21.6.HRMS(ESI)m/zcalcdfor C 17 H 14 O 2 [M+Na] + 273.0883,found 273.0884。
Example 2: synthesis of 5, 7-dimethylflavone
To the reaction flask was added 4, 6-dimethylbenzofuran-2, 3-dione (0.2 mmol), phenylacetylene (0.3 mmol), 1, 3-bis (diphenylphosphine) propane (0.01 mmol), bis (1, 5-cyclooctadiene) nickel (0.01 mmol), and dissolved in toluene (2 mL) under nitrogen. The reaction is completed after 12 hours of normal pressure reaction at 120 ℃. Removing the reaction solvent, and separating and purifying by column chromatography to obtain the target product 5, 7-dimethylflavone: white solid, 23.5mg, yield 47%.
Example 3: synthesis of 5, 7-dimethylflavone
To the reaction flask was added 4, 6-dimethylbenzofuran-2, 3-dione (0.2 mmol), phenylacetylene (0.3 mmol), 1, 3-bis (diphenylphosphine) ethane (0.01 mmol), bis (1, 5-cyclooctadiene) nickel (0.01 mmol), potassium carbonate (0.2 mmol) and toluene (2 mL) under nitrogen protection. The reaction is completed after 12 hours of normal pressure reaction at 120 ℃. Removing the reaction solvent, and separating and purifying by column chromatography to obtain the target product 5, 7-dimethylflavone: white solid, 29.5mg, 59% yield.
Example 4: synthesis of 5, 7-dimethylflavone
To the reaction flask was added 4, 6-dimethylbenzofuran-2, 3-dione (0.2 mmol), phenylacetylene (0.3 mmol), 1, 3-bis (diphenylphosphine) ethane (0.01 mmol), bis (1, 5-cyclooctadiene) nickel (0.01 mmol), sodium phosphate (0.2 mmol) and toluene (2 mL) under nitrogen protection. The reaction is completed after 12 hours of normal pressure reaction at 120 ℃. Removing the reaction solvent, and separating and purifying by column chromatography to obtain the target product 5, 7-dimethylflavone: white solid, 46.5mg, 93% yield.
Example 5: synthesis of 5, 7-dimethylflavone
To the reaction flask was added 4, 6-dimethylbenzofuran-2, 3-dione (0.2 mmol), phenylacetylene (0.3 mmol), 1, 3-bis (diphenylphosphine) ethane (0.01 mmol), bis (1, 5-cyclooctadiene) nickel (0.01 mmol), potassium fluoride (0.2 mmol) and toluene (2 mL) under nitrogen protection. The reaction is completed after 12 hours of normal pressure reaction at 120 ℃. Removing the reaction solvent, and separating and purifying by column chromatography to obtain the target product 5, 7-dimethylflavone: white solid, 46mg, 92% yield.
Example 6: synthesis of 5, 7-dimethylflavone
To the reaction flask was added 4, 6-dimethylbenzofuran-2, 3-dione (0.2 mmol), phenylacetylene (0.3 mmol), 1, 3-bis (diphenylphosphine) ethane (0.01 mmol), bis (1, 5-cyclooctadiene) nickel (0.01 mmol), sodium acetate (0.2 mmol) and toluene (2 mL) under nitrogen protection. The reaction is completed after 12 hours of normal pressure reaction at 100 ℃. Removing the reaction solvent, and separating and purifying by column chromatography to obtain the target product 5, 7-dimethylflavone: white solid, 17mg, 34% yield.
Example 7: synthesis of 5, 7-dimethylflavone
To the reaction flask was added 4, 6-dimethylbenzofuran-2, 3-dione (0.2 mmol), phenylacetylene (0.3 mmol), 1, 3-bis (diphenylphosphine) ethane (0.01 mmol), bis (1, 5-cyclooctadiene) nickel (0.01 mmol), sodium acetate (0.2 mmol) and toluene (2 mL) under nitrogen protection. The reaction is completed after the reaction is carried out for 12 hours at the normal pressure and the temperature of 110 ℃. Removing the reaction solvent, and separating and purifying by column chromatography to obtain the target product 5, 7-dimethylflavone: white solid, 18mg, 36% yield.
Example 8: synthesis of 5, 7-dimethylflavone
To the reaction flask was added 4, 6-dimethylbenzofuran-2, 3-dione (0.2 mmol), phenylacetylene (0.3 mmol), 1, 3-bis (diphenylphosphine) ethane (0.01 mmol), bis (1, 5-cyclooctadiene) nickel (0.01 mmol), sodium dihydrogen phosphate (0.2 mmol) and dissolved in toluene (2 mL) under nitrogen. The reaction is completed after 12 hours of normal pressure reaction at 120 ℃. Removing the reaction solvent, and separating and purifying by column chromatography to obtain the target product 5, 7-dimethylflavone: white solid, 21mg, 42% yield.
Example 9: synthesis of 5, 7-dimethylflavone
To the reaction flask was added 4, 6-dimethylbenzofuran-2, 3-dione (0.2 mmol), phenylacetylene (0.3 mmol), 1, 3-bis (diphenylphosphine) ethane (0.01 mmol), bis (1, 5-cyclooctadiene) nickel (0.01 mmol), dipotassium hydrogen phosphate (0.2 mmol) and toluene (2 mL) under nitrogen protection. The reaction is completed after the reaction is carried out for 12 hours at the normal pressure and the temperature of 110 ℃. Removing the reaction solvent, and separating and purifying by column chromatography to obtain the target product 5, 7-dimethylflavone: white solid, 44mg, yield 84%.
Example 10: synthesis of 5, 7-dimethylflavone
To the reaction flask was added 4, 6-dimethylbenzofuran-2, 3-dione (0.2 mmol), phenylacetylene (0.3 mmol), 1, 3-bis (diphenylphosphine) ethane (0.01 mmol), bis (1, 5-cyclooctadiene) nickel (0.01 mmol), disodium hydrogen phosphate (0.2 mmol) and toluene (2 mL) under nitrogen protection. The reaction is completed after the reaction is carried out for 12 hours at the normal pressure and the temperature of 110 ℃. Removing the reaction solvent, and separating and purifying by column chromatography to obtain the target product 5, 7-dimethylflavone: white solid, 18mg, yield 88%.
Example 11:
the synthesis of 5, 7-dimethyl-4' -n-butyl flavone has the following structural formula:
to the reaction flask was added 4, 6-dimethylbenzofuran-2, 3-dione (0.2 mmol), 4-n-butylphenylacetylene (0.3 mmol), 1, 3-bis (diphenylphosphine) ethane (0.01 mmol), bis (1, 5-cyclooctadiene) nickel (0.01 mmol), potassium acetate (0.2 mmol) and toluene (2 mL) under nitrogen atmosphere. The reaction is completed after 12 hours of normal pressure reaction at 120 ℃. Removing the reaction solvent, and separating and purifying by column chromatography to obtain the target product 5, 7-diMethyl-4' -n-butylflavone: white solid, 60.6mg, 99% yield. 1 H NMR(400MHz,CDCl 3 )δ7.80(d,J＝7.7Hz,2H),7.31(d,J＝7.7Hz,2H),7.19(s,1H),6.94(s,1H),6.66(s,1H),2.85(s,3H),2.68(t,J＝7.7Hz,3H),2.43(s,3H),1.68–1.60(m,2H),1.38(td,J＝14.5,6.9Hz,2H),0.95(t,J＝7.3Hz,3H). 13 C NMR(101MHz,CDCl 3 )δ180.5,161.6,157.9,146.8,143.6,140.6,129.2,129.1,129.0,126.1,120.1,115.9,108.2,35.6,33.3,22.6,22.3,21.6,13.9.HRMS(ESI)m/zcalcdfor C 21 H 22 O 2 [M+H] + 307.1693,found 307.1689。
Example 12:
the synthesis of 5, 7-dimethyl-3' -fluoro flavone has the following structural formula:
to the reaction flask was added 4, 6-dimethylbenzofuran-2, 3-dione (0.2 mmol), 3-fluorophenylacetylene (0.3 mmol), 1, 3-bis (diphenylphosphine) ethane (0.01 mmol), bis (1, 5-cyclooctadiene) nickel (0.01 mmol), potassium acetate (0.2 mmol) and dissolved in toluene (2 mL) under nitrogen atmosphere. The reaction is completed after 12 hours of normal pressure reaction at 120 ℃. Removing the reaction solvent, and separating and purifying by column chromatography to obtain the target product 5, 7-dimethyl-3' -fluoroflavone: white solid, 50.9mg, yield 95%. 1 H NMR(400MHz,CDCl 3 )δ7.64(d,J＝7.8Hz,1H),7.57(d,J＝9.7Hz,1H),7.46(dd,J＝13.9,8.0Hz,1H),7.24–7.12(m,2H),6.94(s,1H),6.65(s,1H),2.82(s,3H),2.42(s,3H). 13 C NMR(101MHz,CDCl 3 )δ180.2,163.0(d,J＝247.1Hz),δ159.8(d,J＝2.6Hz),157.7,144.0,140.6,134.0(d,J＝7.9Hz),130.6(d,J＝8.2Hz),129.3,121.7(d,J＝2.9Hz),120.0,118.1(d,J＝21.2Hz),115.9,113.1(d,J＝23.8Hz),109.2,22.5,21.6. 19 F NMR(282MHz,CDCl 3 )δ-111.54.HRMS(ESI)m/zcalcdfor C 17 H 13 FO 2 [M+Na] + 291.0790,found 291.0788。
Example 13:
the synthesis of 5, 7-dimethyl-2- (1-naphthyl) -4H-1-benzopyran-4-ketone has the following structural formula:
to the reaction flask was added 4, 6-dimethylbenzofuran-2, 3-dione (0.2 mmol), 1-ethynylnaphthalene (0.3 mmol), 1, 3-bis (diphenylphosphine) ethane (0.01 mmol), bis (1, 5-cyclooctadiene) nickel (0.01 mmol), potassium acetate (0.2 mmol) and dissolved in toluene (2 mL) under nitrogen. The reaction is completed after 12 hours of normal pressure reaction at 120 ℃. After the reaction solvent is removed, the target product 5, 7-dimethyl-2- (1-naphthyl) -4H-1-benzopyran-4-ketone is obtained through column chromatography separation and purification: white solid, 58.2mg, 97% yield. 1 H NMR(400MHz,CDCl 3 )δ8.21–8.13(m,1H),8.02(d,J＝8.2Hz,1H),7.96(dd,J＝5.9,3.2Hz,1H),7.76(d,J＝7.1Hz,1H),7.58(dd,J＝8.5,5.5Hz,3H),7.17(s,1H),7.02(s,1H),6.59(s,1H),2.93(s,3H),2.45(s,3H). 13 C NMR(101MHz,CDCl 3 )δ180.3,163.4,158.3,143.9,140.8,133.8,131.3,130.6,130.5,129.3,128.7,127.8,127.3,126.5,125.1,125.0,120.1,116.1,114.2,22.7,21.6.HRMS(ESI)m/zcalcdfor C 21 H 16 O 2 [M+H] + 301.1223,found 301.1225。
Example 14:
the synthesis of 5, 7-dimethyl-4' -acetoxyl flavone has the following structural formula:
to the reaction flask was added 4, 6-dimethylbenzofuran-2, 3-dione (0.2 mmol), 4-ethynylphenyl acetate (0.3 mmol), 1, 3-bis (diphenylphosphine) ethane (0.01 mmol), bis (1, 5-cyclooctadiene) nickel (0.01 mmol), potassium acetate (0.2 mmol) and dissolved in toluene (2 mL) under nitrogen. The reaction is completed after 12 hours of normal pressure reaction at 120 ℃. Removing the reaction solvent, and separating and purifying by column chromatography to obtain the target product 5, 7-dimethyl-4' -acetoxyflavone: white solid, 50.5mg, 82% yield。 1 H NMR(400MHz,CDCl 3 )δ7.89(d,J＝8.8Hz,1H),7.23(d,J＝8.8Hz,1H),6.93(s,1H),6.64(s,1H),5.29(s,1H),2.83(s,3H),2.41(s,3H),2.33(s,3H). 13 C NMR(101MHz,CDCl 3 )δ180.3,169.0,160.5,157.8,152.9,143.8,140.6,129.2,127.4,122.2,120.0,115.9,108.6,53.4,22.5,21.5,21.1.HRMS(ESI)m/zcalcdfor C 19 H 16 O 4 [M+Na] + 331.0939,found 331.0939。
Example 15:
the synthesis of 5, 7-dimethyl-6-chloroflavone has the following structural formula:
to the reaction flask was added 4, 6-dimethyl-6-chlorobenzofuran-2, 3-dione (0.2 mmol), phenylacetylene (0.3 mmol), 1, 3-bis (diphenylphosphine) ethane (0.01 mmol), bis (1, 5-cyclooctadiene) nickel (0.01 mmol), potassium acetate (0.2 mmol) and toluene (2 mL) under nitrogen. The reaction is completed after 12 hours of normal pressure reaction at 120 ℃. Removing the reaction solvent, and separating and purifying by column chromatography to obtain the target product 5, 7-dimethyl-6-chloroflavone: white solid, 44.3mg, yield 78%. 1 H NMR(400MHz,CDCl 3 )δ7.85(d, J ＝7.2Hz,2H),7.50(d, J ＝6.4Hz,3H),7.29(s,1H),6.68(s,1H),2.98(s,3H),2.49(s,3H). 13 C NMR(101MHz,CDCl 3 )δ179.7,161.1,155.6,142.4,138.2,132.7,131.4,131.3,129.0,126.0,121.2,117.5,108.7,21.9,18.0.HRMS(ESI)m/zcalcdfor C 17 H 13 ClO 2 [M+Na] + 307.0496,found 307.0496。
Example 16:
the synthesis of 5, 7-dimethyl-3-acetyl flavone has the following structural formula:
under the protection of nitrogen, 4, 6-dimethyl benzofuran-2, 3-dione is added into a reaction flask0.2 mmol), 4-phenyl-3-butyn-2-one (0.3 mmol), 1, 3-bis (diphenylphosphine) ethane (0.02 mmol), bis (1, 5-cyclooctadiene) nickel (0.02 mmol), were dissolved in toluene (2 mL). The reaction is completed after 12 hours of normal pressure reaction at 120 ℃. Removing the reaction solvent, and separating and purifying by column chromatography to obtain the target product 5, 7-dimethyl-3-acetyl flavone: white solid, 52.6mg, yield 90%. 1 H NMR(400MHz,CDCl 3 )δ7.61–7.53(m,2H),7.47–7.37(m,3H),7.07(s,1H),6.91(s,1H),2.75(s,3H),2.35(s,3H),2.33(s,3H). 13 C NMR(101MHz,CDCl 3 )δ201.2,177.8,160.1,157.5,144.5,141.0,131.8,131.3,129.6,128.8,128.4,125.8,119.5,115.9,32.3,22.5,21.6.HRMS(ESI)m/zcalcdfor C 19 H 16 O 3 [M+H] + 293.1172,found293.1175。
Example 17-example 33: reaction substrate, catalyst applicability
The invention has wide substrate and catalyst applicability, and adopts the reaction conditions: substituted oxo-isatoic (0.2 mmol), substituted phenylacetylene (0.3 mmol), bis (1, 5-cyclooctadiene) nickel and 1, 3-bis (diphenylphosphine) ethane (ratio 1:1, mmol), toluene (2 mL), solvent, and at 120℃for 12 hours; can obtain the flavonoid compound with higher yield.
Example 17-example 33 when R in the flavonoids of the target product 1 、R 2 、R 3 When the catalyst amount (mmol relative to the substrate) was different for the different substituents, the yields are shown in Table 1.
TABLE 1 yield of flavonoids (%)
| Implementation of the embodimentsExample(s) | R 1 | R 2 | R 3 | Potassium acetate | Nickel catalyst | Yield rate |
| 17 | 4' -methyl group | 5, 7-dimethyl | Hydrogen gas | 1.0 | 5％ | 99 |
| 18 | 4' -tert-butyl group | 5, 7-dimethyl | Hydrogen gas | 1.0 | 5％ | 99 |
| 19 | 3' -methyl group | 5, 7-dimethyl | Hydrogen gas | 1.0 | 5％ | 99 |
| 20 | 4' -phenyl group | 5, 7-dimethyl | Hydrogen gas | 1.0 | 5％ | 78 |
| 21 | 2' -fluoro | 5, 7-dimethyl | Hydrogen gas | 1.0 | 5％ | 84 |
| 22 | 2' -chloro | 5, 7-dimethyl | Hydrogen gas | 1.0 | 5％ | 96 |
| 23 | 4' -tert-Butyldimethylsiloxy | 5, 7-dimethyl | Hydrogen gas | 1.0 | 5％ | 88 |
| 24 | 4' -acetyl group | 5, 7-dimethyl | Hydrogen gas | 1.0 | 5％ | 88 |
| 25 | 4' -Boc-imino | 5, 8-dimethyl | Hydrogen gas | 1.0 | 5％ | 71 |
| 26 | 4' -cyano group | 5, 7-dimethyl | Hydrogen gas | 1.0 | 5％ | 57 |
| 27 | 4' -isopropoxy group | 5, 7-dimethyl | Hydrogen gas | 1.0 | 5％ | 72 |
| 28 | Hydrogen gas | 5, 8-dimethyl | Hydrogen gas | 1.0 | 5％ | 93 |
| 29 | Hydrogen gas | 5,7, 8-trimethyl | Hydrogen gas | 1.0 | 5％ | 95 |
| 30 | Hydrogen gas | 5, 7-dimethyl | Acetyl group | 0 | 10％ | 90 |
| 31 | 4' -n-butyl group | 5, 7-dimethyl | Acetyl group | 0 | 10％ | 96 |
| 32 | 4' -tert-Butyldimethylsiloxy | 5, 7-dimethyl | Acetyl group | 0 | 10％ | 96 |
| 33 | Hydrogen gas | 5, 7-dimethyl | Benzoyl group | 0 | 10％ | 92 |
Comparative example 1: synthesis of 5, 7-dimethylflavone
Catalytic with palladium catalytic system: to the reaction flask was added 4, 6-dimethylbenzofuran-2, 3-dione (0.2 mmol), phenylacetylene (0.3 mmol), tetrakis (triphenylphosphine) palladium (0.01 mmol), potassium acetate (0.2 mmol) and toluene (2 mL) under nitrogen. The reaction was carried out at 120℃under normal pressure for 12 hours. No target product is generated.
Comparative example 2: synthesis of 5, 7-dimethylflavone
Catalyzed by cuprous iodide: to the reaction flask was added 4, 6-dimethylbenzofuran-2, 3-dione (0.2 mmol), phenylacetylene (0.3 mmol), 1, 3-bis (diphenylphosphine) ethane (0.02 mmol), cuprous iodide (0.02 mmol), potassium acetate (0.2 mmol), and toluene (2 mL) under nitrogen. The reaction was carried out at 120℃under normal pressure for 12 hours. Removing the reaction solvent, and separating and purifying by column chromatography to obtain the target product 5, 7-dimethylflavone: white solid, 5mg, 10% yield.
Comparative example 3: synthesis of 5, 7-dimethylflavone
Catalytic with rhodium catalytic system: to the reaction flask was added 4, 6-dimethylbenzofuran-2, 3-dione (0.2 mmol), phenylacetylene (0.3 mmol), 1, 3-bis (diphenylphosphine) ethane (0.01 mmol), rhodium bis (1, 5-cyclooctadiene) tetrafluoroborate (0.01 mmol), potassium acetate (0.2 mmol) and toluene (2 mL) under nitrogen atmosphere. The reaction was carried out at 120℃under normal pressure for 12 hours. No target product is generated.
Comparative example 4: synthesis of 5, 7-dimethylflavone
Catalytic with ruthenium catalytic system: to the reaction flask was added 4, 6-dimethylbenzofuran-2, 3-dione (0.2 mmol), phenylacetylene (0.3 mmol), tris (triphenylphosphine) ruthenium dichloride (0.01 mmol), potassium acetate (0.2 mmol) and toluene (2 mL) under nitrogen. The reaction was carried out at 120℃under normal pressure for 12 hours. No target product is generated.
According to the above examples and comparative examples, the present invention provides a method for preparing a flavonoid compound, which comprises the steps of taking oxo-indigo red or oxo-indigo red substituted on a benzene ring, taking phenylacetylene or substituted phenylacetylene as a reaction substrate, taking a nickel catalyst and a ligand as a catalyst, taking an inorganic base as a cocatalyst, and carrying out a cyclization reaction after removing carbon monoxide through nickel catalysis in a solvent environment. The method has the advantages of simple reaction process operation and low cost, and strong acid, strong alkali, strong corrosiveness and toxic reagents are not needed; high reaction efficiency, high yield, less byproducts, no need of noble metals and expensive ligands. Meanwhile, the substituent effect of the raw materials has little influence on the reaction, and can synthesize compounds containing flavone skeletons with various substitutions and structures.
The above examples are preferred embodiments of the present invention, but the embodiments of the present invention are not limited to the above examples, and any other changes, modifications, substitutions, combinations, and simplifications that do not depart from the spirit and principle of the present invention should be made in the equivalent manner, and the embodiments are included in the protection scope of the present invention.
Claims (2)
1. A preparation method of flavonoid compounds is characterized in that: taking a compound I and a compound II as reaction substrates, using a nickel catalyst and a ligand as catalysts, taking alkali as a cocatalyst, and carrying out cyclization reaction after removing carbon monoxide through nickel catalysis in a solvent environment to obtain flavonoid compounds; the reaction equation is shown as follows:
the ligand is selected from 1, 2-bis (diphenylphosphine) ethane and 1, 3-bis (diphenylphosphine) propane;
the nickel catalyst is selected from bis (1, 5-cyclooctadiene) nickel;
in the alkali, the cation is alkali metal ion, and the anion is carbonate ion, phosphate ion, hydrogen phosphate ion, dihydrogen phosphate ion, fluoride ion and carboxylate ion with 1-10 carbon atoms;
the solvent is at least one of toluene, dimethylbenzene, mesitylene, chlorobenzene and nitrobenzene;
the compound I has one or more hydrogen on benzene ring thereof being replaced by R 2 Substitution; the R is 2 Identical or identicalDifferent groups are respectively selected from halogen atoms, trifluoromethyl, alkyl groups with 1-10 carbon atoms and alkoxy groups with 1-10 carbon atoms;
the compound II has one or more hydrogen on the aromatic ring Ar being replaced by R 1 Substitution; the R is 1 The same or different is respectively selected from halogen atom, trifluoromethyl, alkyl with 1-10 carbon atoms, cycloalkyl with 3-10 carbon atoms, alkoxy with 1-10 carbon atoms, trialkylsilyl with 1-5 carbon atoms, trialkylsiloxy with 1-5 carbon atoms, -CN, -OCOR, -COR, -NH 2 or-NHR 'or-NR' 2 Aryl with 6-20 carbon atoms; r is selected from alkyl with 1-10 carbon atoms; r ' is-COOR ' '; r '' is selected from alkyl with 1-10 carbon atoms;
the compound II has hydrogen on ethynyl group of R 3 Substitution, said R 3 The same or different are respectively selected from alkyl groups with 1-10 carbon atoms, -COR; r is selected from aryl with 6 carbon atoms and alkyl with 1-10 carbon atoms;
the aromatic ring Ar of the compound II is selected from phenyl and naphthyl.
2. The method for preparing a flavonoid compound according to claim 1, wherein: the molar ratio of the compound I to the compound II is 1:1.2-1:2; the dosage of the nickel catalyst is 5-10mol% of the dosage of the compound I; the amount of the ligand is 5-10mol% of the amount of the compound I.
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