CN110713475B - Novel synthesis method of polysubstituted 4, 5, 6, 7-tetrahydrobenzofuran - Google Patents
Novel synthesis method of polysubstituted 4, 5, 6, 7-tetrahydrobenzofuran Download PDFInfo
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- CN110713475B CN110713475B CN201911072910.XA CN201911072910A CN110713475B CN 110713475 B CN110713475 B CN 110713475B CN 201911072910 A CN201911072910 A CN 201911072910A CN 110713475 B CN110713475 B CN 110713475B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
- C07D307/86—Benzo [b] furans; Hydrogenated benzo [b] furans with an oxygen atom directly attached in position 7
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
- C07D307/82—Benzo [b] furans; Hydrogenated benzo [b] furans with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
- C07D307/84—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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- 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
- C07D409/06—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 linked by a carbon chain containing only aliphatic carbon atoms
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Abstract
The invention discloses a brand new synthesis method of polysubstituted 4, 5, 6, 7-tetrahydrobenzofuran, which takes 2-hydroxy-1, 4-diketone as an initial raw material to perform series reaction with an electricity-rich substrate under the catalysis of acid to generate the polysubstituted 4, 5, 6, 7-tetrahydrobenzofuran. The electricity-rich substrate is one of alcohol, amide, sulfonamide, furan, thiophene, pyrrole, benzofuran, benzothiophene, indole, methoxy substituted benzene and the like. The method has simple reaction conditions and extremely wide substrate applicability, can be used for synthesizing a series of polysubstituted 4, 5, 6, 7-tetrahydrobenzofuran, and is expected to be used for constructing molecular libraries of related active molecules in the fields of medicines, pesticides and the like.
Description
Technical Field
The invention relates to the field of organic chemical synthesis, in particular to a brand new synthesis method of polysubstituted 4, 5, 6, 7-tetrahydrobenzofuran.
Background
4, 5, 6, 7-tetrahydrobenzofuran is a more important cyclized skeleton and has potential application in the fields of medicines and pesticides. However, the traditional synthesis of 4, 5, 6, 7-tetrahydrobenzofuran has certain limitations: on one hand, the method is often required to be carried out through multi-step reaction, the total yield is low, and the use of transition metal is often involved, so that trace transition metal is remained in the product; on the other hand, there is currently no more than a general synthetic method for 4, 5, 6, 7-tetrahydrobenzofuran substituted at the α -position or the 7-position of the 2-position.
Disclosure of Invention
In order to solve the problems, the invention provides a brand-new synthesis method of polysubstituted 4, 5, 6, 7-tetrahydrobenzofuran, which has simple reaction conditions and extremely wide substrate applicability, can be used for synthesizing a series of polysubstituted 4, 5, 6, 7-tetrahydrobenzofuran and is expected to be used for constructing molecular libraries of related active molecules in the fields of medicines, pesticides and the like.
In order to achieve the purpose, the invention adopts the technical scheme that:
a novel synthesis method of polysubstituted 4, 5, 6, 7-tetrahydrobenzofuran uses 2-hydroxy-1, 4-diketone as an initial raw material to perform a series reaction with an electricity-rich substrate under the catalysis of acid to generate the polysubstituted 4, 5, 6, 7-tetrahydrobenzofuran.
Further, the electricity-rich substrate is one of alcohol, amide, sulfonamide, furan, thiophene, pyrrole, benzofuran, benzothiophene, indole, methoxy-substituted benzene or derivatives of the above substrates.
Further, when the R1 group in the electron-rich substrate is methyl, the electron-rich substrate reaction is at the 7-position of 4, 5, 6, 7-tetrahydrobenzofuran, and can be used for synthesizing a series of 2, 3, 7-trisubstituted-4, 5, 6, 7-tetrahydrobenzofuran.
Further, when the R1 group in the electron-rich substrate is other alkyl group, the electron-rich substrate reacts at the alpha position of the 2-position of 4, 5, 6, 7-tetrahydrobenzofuran, and can be used for synthesizing a series of 2, 3-disubstituted-4, 5, 6, 7-tetrahydrobenzofuran.
The invention provides a universal simple method for multi-step or difficult-to-synthesize multi-substituted 4, 5, 6, 7-tetrahydrobenzofuran in the traditional method, the reaction does not involve the use of any transition metal, trace metal inclusion in the product can be well avoided, and meanwhile, the substrate of the route has very wide applicability and is expected to be used for constructing molecular libraries of related active molecules in the fields of medicines, pesticides and the like.
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FIG. 1 is a synthesis scheme of a novel synthesis method of polysubstituted 4, 5, 6, 7-tetrahydrobenzofuran according to an embodiment of the present invention.
FIG. 2 is a reaction mechanism diagram of a novel synthesis method of polysubstituted 4, 5, 6, 7-tetrahydrobenzofuran according to an embodiment of the present invention.
Detailed Description
The present invention will be described in detail with reference to specific examples. The following examples will assist those skilled in the art in further understanding the invention, but are not intended to limit the invention in any way. It should be noted that variations and modifications can be made by persons skilled in the art without departing from the spirit of the invention. All falling within the scope of the present invention.
The embodiment of the invention provides a brand-new synthesis method of polysubstituted 4, 5, 6, 7-tetrahydrobenzofuran, which takes 2-hydroxy-1, 4-diketone as an initial raw material to perform a series reaction with an electricity-rich substrate under the catalysis of acid to generate polysubstituted 4, 5, 6, 7-tetrahydrobenzofuran; the electricity-rich substrate is one of alcohol, amide, sulfonamide, furan, thiophene, pyrrole, benzofuran, benzothiophene, indole, methoxy substituted benzene and the like. The reaction mechanism of this reaction is shown in fig. 2: under the catalysis of acid, 1 generates a key intermediate through cyclization and dehydration, when R is1When the hydrogen is generated, the intermediate and the electricity-enriched substrate generate 1, 6-conjugate addition reaction to generate a product 2. When R is1In the case of alkyl, the intermediate undergoes a Fridel-Craft type reaction with an electron rich substrate to produce product 3.
Example 1
Synthesis of 2, 3, 7-trisubstituted-4, 5, 6, 7-tetrahydrobenzofuran: 2-hydroxy-1, 4-diketone (1, 0.2mmol), 1, 2-dichloroethane (2.0mL), a nucleophilic reagent (0.4mmol), and 2, 2, 2-trifluoroacetic acid (0.04mmol) are sequentially added into a 38mL specification of Xinweier pressure tube (with a magnetic stirrer added), a tetrafluoroethylene plug is plugged, the pressure tube is stirred in an oil bath at 80 ℃ for 48 hours, the reaction is stopped, the reaction solution is concentrated, and the product 2 is obtained by column chromatography. Note: when methanol or ethanol is used as a reaction reagent, 2 ml of methanol or ethanol is directly used as a reaction solvent, and 1, 2-dichloroethane is not used.
The substrate of the reaction has a wide application range, a part of applicable substrates are shown in table 1, and the substrates rich in electricity, such as alcohol, amide, furan, indole and the like can participate in the reaction. In Table 1 TFA means 2, 2, 2-trifluoroacetic acid, nucleotides means various types of electron-rich substrates, DCE means 1, 2-dichloroethane, "or as solvent" means "or used as solvent".
TABLE 1 partial synthesis of 2, 3, 7-trisubstituted 4, 5, 6, 7-tetrahydrobenzofuran shows
Example 2
Synthesis of 2, 3-disubstituted 4, 5, 6, 7-tetrahydrobenzofuran: 2-hydroxy-1, 4-di-ketone (1, 0.2mmol), 1, 2-dichloroethane (2.0mL), nucleophile (0.4mmol), and boron trifluoride etherate (0.04mmol) were sequentially added to 38mL Xinweier pressure tube (magnetic stirrer was added). Thereafter, a plug of tetrafluoroethylene was inserted, and the pressure-resistant pipe was stirred in an oil bath at 90 ℃ for 24 hours. After that, the reaction was stopped, and the reaction solution was concentrated and subjected to column chromatography to obtain a product 3. Note: when methanol or ethanol is used as a reaction reagent, 2 ml of methanol or ethanol is directly used as a reaction solvent, and 1, 2-dichloroethane is not used.
The substrate of the reaction has a very wide application range, a part of applicable substrates are shown in table 2, and the substrates rich in electricity, such as alcohol, amide, furan, thiophene, benzofuran, benzothiophene, indole and the like, can participate in the reaction. Nucleophiles in Table 2 mean various types of electron-rich substrates, DCE means 1, 2-dichloroethane, "or as solvent" means "or used as solvent".
TABLE 2, 3-disubstituted 4, 5, 6, 7-tetrahydrobenzofuran synthesis product display (one of each substrate is selected as representative)
It is noted that many protonic acid or Lewis acid catalysts can catalyze the reaction, and the reaction can be carried out by using other organic solvents or slightly changing the temperature, and the 2, 2, 2-trifluoroacetic acid and boron trifluoride diethyl etherate shown in the patent have better catalytic effects.
The foregoing description of specific embodiments of the present invention has been presented. It is to be understood that the present invention is not limited to the specific embodiments described above, and that various changes or modifications may be made by one skilled in the art within the scope of the appended claims without departing from the spirit of the invention. The embodiments and features of the embodiments of the present application may be combined with each other arbitrarily without conflict.
Claims (3)
1. A novel synthesis method of polysubstituted 4, 5, 6, 7-tetrahydrobenzofuran is characterized by comprising the following steps: 2-hydroxy-1, 4-diketone is taken as an initial raw material and is subjected to a series reaction with an electricity-rich substrate under the catalysis of acid to generate polysubstituted 4, 5, 6, 7-tetrahydrobenzofuran;
the electricity-rich substrate is one of alcohol, amide, sulfonamide, furan, thiophene, pyrrole, benzofuran, benzothiophene, indole, methoxy substituted benzene or derivatives of the above substrates;
the structural formula of the 2-hydroxy-1, 4-diketone is as follows:
2. the novel process for the synthesis of polysubstituted 4, 5, 6, 7-tetrahydrobenzofuran according to claim 1, wherein: when R in the starting material1When the group is methyl, the electricity-rich substrate reacts at the 7-position of 4, 5, 6, 7-tetrahydrobenzofuran, and can be used for synthesizing a series of 2, 3, 7-trisubstituted 4, 5, 6, 7-tetrahydrobenzofuran.
3. The novel process for the synthesis of polysubstituted 4, 5, 6, 7-tetrahydrobenzofuran according to claim 1, wherein: when R in the starting material1When the group is other alkyl group, the electricity-rich substrate reacts at the alpha position of the 2 position of 4, 5, 6, 7-tetrahydrobenzofuran, and can be used for synthesizing a series of 2, 3-disubstituted 4, 5, 6, 7-tetrahydrobenzofuran.
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| CN109912579A (en) * | 2019-01-23 | 2019-06-21 | 华中科技大学 | A kind of preparation method of 2,2- disubstituted tetrahydrofuran derivatives |
| CN110003187A (en) * | 2019-05-10 | 2019-07-12 | 南京工业大学 | Polyfluoroalkyl substituted benzofuran compound and preparation method thereof |
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| CN109912579A (en) * | 2019-01-23 | 2019-06-21 | 华中科技大学 | A kind of preparation method of 2,2- disubstituted tetrahydrofuran derivatives |
| CN110003187A (en) * | 2019-05-10 | 2019-07-12 | 南京工业大学 | Polyfluoroalkyl substituted benzofuran compound and preparation method thereof |
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