A fully substituted alkyl alkenyl ether, its preparation method and application

Abstract

This invention discloses a fully substituted alkyl alkenyl ether, its preparation method, and its applications. The preparation method includes the following steps: dissolving a catalyst, an additive, a 1-alkyne or polyfluorobenzene, or gem-difluorocyclopropane in a solvent, heating to a set temperature, allowing the reaction to proceed fully, and purifying to obtain the desired fully substituted alkyl alkenyl ether. The additive is one of an alkoxide, an alcohol, or an alkoxide mixed in any proportion. This invention provides a one-step method to obtain a fully substituted alkyl alkenyl ether with a defined configuration, and the preparation method is simple. The catalyst, ligand, additive, solvent, and other raw materials used in the preparation method are all commercially available or readily available, and the reaction conditions are mild, simple, and easy to operate.

Description

Technical Field

[0001] This invention relates to the field of compound synthesis technology, specifically to a fully substituted alkyl alkenyl ether, its preparation method, and its application. Background Technology

[0002] Alkyl alkenyl ethers are a common class of organic compounds with broad application prospects in basic chemical research, industrial production, and drug development. Some bioactive alkyl alkenyl ethers can be used as drug molecules for pharmacological research and drug development; others with antibacterial, anti-inflammatory, and antitumor activities are widely used in antibiotics and anticancer drugs. Due to their low viscosity and high solubility, alkyl alkenyl ethers can improve the stability of industrial chemicals and are often used as raw materials for surfactants, lubricants, and antioxidants. Because they readily undergo polymerization to form polymers, they are commonly used in the manufacture of adhesives, varnishes, paints, food packaging materials, tablet coatings, and fillers.

[0003] Currently, low-substituted alkyl alkenyl ethers can be obtained through various synthetic methods, the most common being alkylation and alkenylation reactions. Common methods in alkylation reactions include alkyl halogenation, reactions of alkyl metal reagents with haloalkenes, and oxidation of alkyl sulfides. These methods effectively introduce alkyl groups into alkenyl ethers, forming alkyl alkenyl ethers. Common methods in alkenylation reactions include acid-catalyzed reactions of alkenes with alcohols, acid-catalyzed reactions of alkenes with ethers, and metal-catalyzed reactions of alkenes with alcohols. These methods introduce alkenes into ether molecules, forming alkyl alkenyl ethers.

[0004] Existing preparation methods are generally complex and prone to introducing impurities. Even the simplest method requires two steps: first, using alkynes, alcohols, and high-valent iodine reagents as raw materials to prepare fully substituted alkenyl ethers with high-valent iodine substituents; second, replacing the high-valent iodine substituents with carbon atoms via a transition metal-catalyzed carbon-carbon coupling reaction, ultimately yielding fully substituted alkyl alkenyl ethers, such as... Figure 1 As shown. However, this method requires two purification processes, and its raw materials, such as high-valent iodine reagents, are not commercially available and need to be prepared separately; the second step requires the use of noble metal catalysts and special ligands, which is costly and lacks substrate universality. Summary of the Invention

[0005] This invention addresses the problems existing in the prior art by providing a fully substituted alkyl alkenyl ether, its preparation method, and its application. The fully substituted alkyl alkenyl ether with a defined configuration is prepared in one step.

[0006] The technical solution adopted in this invention is:

[0007] A fully substituted alkyl alkenyl ether having one of the following structures:

[0008]

[0009] R 1 It is one of methyl, ethyl, n-hexyl, cyclohexyl, phenyl, substituted phenyl, benzyl, and styryl;

[0010] R 2 It is one of methyl, ethyl, n-hexyl, cyclohexyl, and benzyl;

[0011] R 3 It is one of hydrogen atom, methyl, ethyl, propyl, cyclopropyl, n-pentyl, tert-pentyl, n-hexyl, cyclohexyl, adamantyl, phenyl, benzyl, and styryl;

[0012] R 4 It is one of the following: hydrogen atom, fluorine atom, methyl, ethyl, propyl, cyclopropyl, n-pentyl, tert-pentyl, n-hexyl, cyclohexyl, adamantyl, phenyl, benzyl, styryl, methoxy, tert-butoxy, and benzyloxy.

[0013] R 5 It is one of the following: hydrogen atom, fluorine atom, methyl, ethyl, propyl, cyclopropyl, n-pentyl, tert-pentyl, n-hexyl, cyclohexyl, adamantyl, phenyl, benzyl, styryl, methoxy, tert-butoxy, and benzyloxy.

[0014] R 6 It is one of the following: hydrogen atom, fluorine atom, methyl, ethyl, propyl, cyclopropyl, n-pentyl, tert-pentyl, n-hexyl, cyclohexyl, adamantyl, phenyl, benzyl, styryl, methoxy, tert-butoxy, and benzyloxy.

[0015] R 7 It is one of the following: hydrogen atom, fluorine atom, methyl, ethyl, propyl, cyclopropyl, n-pentyl, tert-pentyl, n-hexyl, cyclohexyl, adamantyl, phenyl, benzyl, styryl, methoxy, tert-butoxy, and benzyloxy.

[0016] R 8 It is one of the following: hydrogen atom, fluorine atom, methyl, ethyl, propyl, cyclopropyl, n-pentyl, tert-pentyl, n-hexyl, cyclohexyl, adamantyl, phenyl, benzyl, styryl, methoxy, tert-butoxy, and benzyloxy.

[0017] R 9 It is one of the following: hydrogen atom, fluorine atom, methyl, ethyl, propyl, cyclopropyl, n-pentyl, tert-pentyl, n-hexyl, cyclohexyl, adamantyl, phenyl, benzyl, styryl, methoxy, tert-butoxy, and benzyloxy.

[0018] R 10It is one of the following: hydrogen atom, fluorine atom, methyl, ethyl, propyl, cyclopropyl, n-pentyl, tert-pentyl, n-hexyl, cyclohexyl, adamantyl, phenyl, benzyl, styryl, methoxy, tert-butoxy, and benzyloxy.

[0019] A method for preparing a fully substituted alkyl alkenyl ether includes the following steps:

[0020] The catalyst, additives, 1-alkyne or polyfluorobenzene, gem-difluorocyclopropane are dissolved in a solvent, heated to a set temperature value, and allowed to react fully. After purification, the desired fully substituted alkyl alkenyl ether can be obtained.

[0021] The additive is one of the following: an alkoxide, an alcohol, and an alkoxide mixed in any proportion.

[0022] Furthermore, the catalyst is a copper metal compound.

[0023] Furthermore, the alkoxide is one of lithium tert-butoxide, sodium tert-butoxide, potassium tert-butoxide, and sodium bis(trimethylsilyl)amino.

[0024] Furthermore, the molar ratio of the catalyst to gem-difluorocyclopropane is 0.00001 to 1:1; the molar ratio of gem-difluorocyclopropane to the additive is 1:1 to 10; and the molar ratio of gem-difluorocyclopropane to 1-alkyne or polyfluorobenzene is 1:1 to 10.

[0025] Furthermore, the reaction temperature is 55℃~65℃, and the reaction time is 0.5~72 hours.

[0026] Furthermore, the copper metal compound is one of cuprous chloride, cuprous bromide, cuprous iodide, cuprous oxide, cuprous acetate, cuprous cyanide, cuprous thiophene-2-carboxylate, copper tetra(acetonitrile)tetrafluoroborate, copper tetra(acetonitrile)trifluoromethanesulfonate, copper tetraethyl cyanate hexafluorophosphate, copper trifluoromethanesulfonate, and benzene in a molar ratio of 2:1, copper chloro[1,3-bis(2,4,6-trimethylyl)imidazolium-2-ylidene], copper chloro[1,3-bis(2,6-diisopropylphenyl)imidazolium-2-ylidene], copper difluoride, copper chloride, copper bromide, copper iodide, copper bis(2-ethylhexanoate), copper bis(2-ethylhexanoate), and copper bis(trifluoromethanesulfonyl)imide.

[0027] Furthermore, the 1-acetylene is octylene.

[0028] Furthermore, the polyfluorobenzene is 2,3,5,6-tetrafluoroanisole.

[0029] Application of a fully substituted alkyl alkenyl ether, wherein the fully substituted alkyl alkenyl ether is introduced as an intermediate into a bioactive molecule.

[0030] The beneficial effects of this invention are:

[0031] (1) The present invention can obtain fully substituted alkyl alkenyl ethers with a defined configuration in one step, and the preparation method is simple;

[0032] (2) The catalysts, ligands, additives, solvents and other raw materials used in the preparation method of the present invention are all commercial or readily available, and the reaction conditions are mild, simple and easy to operate;

[0033] (3) The present invention can introduce fully substituted alkyl alkenyl ether structures with defined configurations into bioactive molecules. Attached Figure Description

[0034] Figure 1 The reaction equations in the prior art are shown in the background section.

[0035] Figure 2 This is the reaction equation for the present invention.

[0036] Figure 3 The 1H NMR spectrum of the fully substituted alkyl alkenyl ether obtained in Example 1 of this invention.

[0037] Figure 4 This is the carbon NMR spectrum of the fully substituted alkyl alkenyl ether obtained in Example 1 of the present invention.

[0038] Figure 5 The 1H NMR spectrum of the fully substituted alkyl alkenyl ether obtained in Example 2 of this invention.

[0039] Figure 6 This is the carbon NMR spectrum of the fully substituted alkyl alkenyl ether obtained in Example 2 of the present invention.

[0040] Figure 7 The 1H NMR spectrum of the fully substituted alkyl alkenyl ether obtained in Example 3 of this invention.

[0041] Figure 8 The image shows the carbon NMR spectrum of the fully substituted alkyl alkenyl ether obtained in Example 3 of this invention.

[0042] Figure 9 The NMR fluorine spectrum of the fully substituted alkyl alkenyl ether obtained in Example 3 of this invention.

[0043] Figure 10 The reaction equation is shown in Example 4 of this invention. Detailed Implementation

[0044] The present invention will be further described below with reference to the accompanying drawings and specific embodiments.

[0045] A fully substituted alkyl alkenyl ether having one of the following structures:

[0046]

[0047] R 1 It is one of methyl, ethyl, n-hexyl, cyclohexyl, phenyl, substituted phenyl, benzyl, and styryl;

[0048] R 2 It is one of methyl, ethyl, n-hexyl, cyclohexyl, and benzyl;

[0049] R 3 It is one of hydrogen atom, methyl, ethyl, propyl, cyclopropyl, n-pentyl, tert-pentyl, n-hexyl, cyclohexyl, adamantyl, phenyl, benzyl, and styryl;

[0050] R 4 It is one of the following: hydrogen atom, fluorine atom, methyl, ethyl, propyl, cyclopropyl, n-pentyl, tert-pentyl, n-hexyl, cyclohexyl, adamantyl, phenyl, benzyl, styryl, methoxy, tert-butoxy, and benzyloxy.

[0051] R 5 It is one of the following: hydrogen atom, fluorine atom, methyl, ethyl, propyl, cyclopropyl, n-pentyl, tert-pentyl, n-hexyl, cyclohexyl, adamantyl, phenyl, benzyl, styryl, methoxy, tert-butoxy, and benzyloxy.

[0052] R 6 It is one of the following: hydrogen atom, fluorine atom, methyl, ethyl, propyl, cyclopropyl, n-pentyl, tert-pentyl, n-hexyl, cyclohexyl, adamantyl, phenyl, benzyl, styryl, methoxy, tert-butoxy, and benzyloxy.

[0053] R 7 It is one of the following: hydrogen atom, fluorine atom, methyl, ethyl, propyl, cyclopropyl, n-pentyl, tert-pentyl, n-hexyl, cyclohexyl, adamantyl, phenyl, benzyl, styryl, methoxy, tert-butoxy, and benzyloxy.

[0054] R 8 It is one of the following: hydrogen atom, fluorine atom, methyl, ethyl, propyl, cyclopropyl, n-pentyl, tert-pentyl, n-hexyl, cyclohexyl, adamantyl, phenyl, benzyl, styryl, methoxy, tert-butoxy, and benzyloxy.

[0055] R 9 It is one of the following: hydrogen atom, fluorine atom, methyl, ethyl, propyl, cyclopropyl, n-pentyl, tert-pentyl, n-hexyl, cyclohexyl, adamantyl, phenyl, benzyl, styryl, methoxy, tert-butoxy, and benzyloxy.

[0056] R 10 It is one of the following: hydrogen atom, fluorine atom, methyl, ethyl, propyl, cyclopropyl, n-pentyl, tert-pentyl, n-hexyl, cyclohexyl, adamantyl, phenyl, benzyl, styryl, methoxy, tert-butoxy, and benzyloxy.

[0057] A method for preparing a fully substituted alkyl alkenyl ether includes the following steps:

[0058] The catalyst, additives, 1-alkyne or polyfluorobenzene, and geminitrocyclopropane are dissolved in a solvent, heated to a set temperature, and allowed to react fully. After purification, the desired fully substituted alkyl alkenyl ether can be obtained. The reaction is carried out under heating and stirring conditions. After the reaction is completed, the ether is purified by silica gel column chromatography.

[0059] The additive is one of the following: an alkoxide, an alcohol, and an alkoxide mixed in any proportion. The alkoxide is one of lithium tert-butoxide, sodium tert-butoxide, potassium tert-butoxide, and sodium bis(trimethylsilyl)amino. The solvent is one of 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane, ethylene glycol dimethyl ether, fluorobenzene, chlorobenzene, toluene, and trifluorotoluene.

[0060] The catalyst is a copper metal compound, which is one of the following: cuprous chloride, cuprous bromide, cuprous iodide, cuprous oxide, cuprous acetate, cuprous cyanide, cuprous thiophene-2-carboxylate, copper tetra(acetonitrile)tetrafluoroborate, copper tetra(acetonitrile)trifluoromethanesulfonate, copper tetraethyl cyanate hexafluorophosphate, copper trifluoromethanesulfonate, and benzene in a molar ratio of 2:1; copper chloro[1,3-bis(2,4,6-trimethylyl)imidazolium-2-ylidene], copper chloro[1,3-bis(2,6-diisopropylphenyl)imidazolium-2-ylidene], copper difluoride, copper chloride, copper bromide, copper iodide, copper bis(2-ethylhexanoate), copper bis(2-ethylhexanoate), and copper bis(trifluoromethanesulfonyl)imide.

[0061] The molar ratio of catalyst to gem-difluorocyclopropane is 0.00001 to 1:1, with the optimal molar ratio being 0.02:1; the molar ratio of gem-difluorocyclopropane to additive is 1:1 to 10, with the optimal molar ratio being 1:4; the molar ratio of gem-difluorocyclopropane to 1-alkyne or polyfluorobenzene is 1:1 to 10, with the optimal molar ratio being 1:2.

[0062] The reaction temperature is 55℃~65℃, and the reaction time is 0.5~72 hours; the concentration of various raw materials in the solvent is 0.1~5.0mol / L.

[0063] Example 1

[0064] A method for preparing a fully substituted alkyl alkenyl ether includes the following steps:

[0065] In a nitrogen-protected glove box, add the following ingredients sequentially to the reaction flask: a magnetic stir bar, 0.3 mmol phenyldifluorocyclopropane, 0.2 mmol / L octyne, 0.004 mmol / L copper(I) chloride [1,3-bis(2,4,6-trimethylyl)imidazolium-2-yl], 0.8 mmol / L sodium tert-butoxide, and 0.4 mL tetrahydrofuran. Seal the flask, remove it from the glove box, and place it on a magnetic stirrer. Stir the reaction mixture at 55°C for 1 hour.

[0066] The resulting reaction solution was transferred to a silica gel chromatography column and eluted with an organic solvent (PE / DCM = 5 / 1) to obtain a colorless liquid (R). f =0.30), with a tested yield of 89% (53.0 mg). The structural formula of the obtained fully substituted alkyl alkenyl ether is as follows:

[0067]

[0068] Its nuclear magnetic resonance hydrogen spectrum 1 H NMR such as Figure 3 As shown in the figure, (400MHz, CDCl3)δ 7.48–7.41(m,2H), 7.32–7.26(m,2H), 7.23–7.18(m,1H), 2.17(t,J=6.9Hz,2H), 2.07(s,3H), 1.44(s,9H), 1.43–1.33(m,2H), 1.32–1.12(m,6H), 0.87(t,J=7.0Hz,3H).

[0069] Its carbon NMR spectrum 13 C NMR such as Figure 4 As shown in the figure, the values ​​of (101MHz, CDCl3) are δ141.2, 131.3, 131.0, 128.5, 127.6, 126.5, 92.9, 79.0, 78.8, 31.3, 29.0, 28.5, 28.0, 22.5, 19.3, 18.1, and 14.1.

[0070] HRMS(ESI,m / z): calcd for C 21 H 30 ONa + [M+Na] + 321.2189, found 321.2186.

[0071] Example 2

[0072] A method for preparing a fully substituted alkyl alkenyl ether includes the following steps:

[0073] In a nitrogen-protected glove box, add the following ingredients sequentially to the reaction flask: a magnetic stir bar, 0.3 mmol phenyldifluorocyclopropane, 0.2 mmol / L octyne, 0.004 mmol / L copper(I) chloride [1,3-bis(2,4,6-trimethylyl)imidazolium-2-yl], 0.8 mmol / L sodium tert-butoxide, and 0.4 mL ethanol. Seal the flask, remove it from the glove box, and place it on a magnetic stirrer. Stir the reaction mixture at 65°C for 1 hour.

[0074] The resulting reaction solution was transferred to a silica gel chromatography column and eluted with an organic solvent (PE / DCM = 5 / 1) to obtain a colorless liquid (R). f =0.30), with a tested yield of 85% (44.9 mg). The structural formula of the obtained fully substituted alkyl alkenyl ether is as follows:

[0075]

[0076] Its nuclear magnetic resonance hydrogen spectrum 1 H NMR such as Figure 5 As shown in the figure, (400MHz, CDCl3)δ 7.57–7.52(m,2H), 7.37–7.31(m,2H), 7.26(m,6H), 4.14(q,J=7.0Hz,2H), 2.17(s,3H), 1.36(t,J=7.0Hz,3H).

[0077] Its carbon NMR spectrum 13 C NMR such as Figure 6 As shown in the figure, the δ values ​​for (101MHz, CDCl3) are 140.9, 134.1, 131.1, 128.5, 128.2, 128.2, 127.7, 127.3, 126.8, 122.9, 93.3, 84.1, 64.9, 17.0, and 15.3.

[0078] HRMS(ESI,m / z): calcd for C 19 H 19 O + [M+H] + 263.1430, found 263.1433.

[0079] Example 3

[0080] A method for preparing a fully substituted alkyl alkenyl ether includes the following steps:

[0081] In a nitrogen-protected glove box, add the following to the reaction flask in sequence: a magnetic stir bar, 0.3 mmol phenyl difluorocyclopropane, 0.2 mmol / L 2,3,5,6-tetrafluoroanisole, 0.004 mmol / L chloro[1,3-bis(2,4,6-trimethylyl)imidazol-2-yl]copper(I), 0.8 mmol / L sodium tert-butoxide, and 0.4 mL tetrahydrofuran. Seal the flask, remove it from the glove box, and place it on a magnetic stirrer. Stir the reaction mixture at 65°C for 1 hour.

[0082] The resulting reaction solution was transferred to a silica gel chromatography column and eluted with an organic solvent (PE / DCM = 5 / 1) to obtain a colorless liquid (R). f =0.30), with a tested yield of 83% (49.1 mg). The structural formula of the obtained fully substituted alkyl alkenyl ether is as follows:

[0083]

[0084] Its nuclear magnetic resonance hydrogen spectrum 1 H NMR such as Figure 7 As shown in the figure, (400MHz, CDCl) 3 )δ7.16–7.10(m,3H), 7.00(dd,J=7.8,1.8Hz,2H), 4.00(t,J=1.5Hz,3H), 2.18(s,3H), 1.23(s,9H).

[0085] Its carbon NMR spectrum 13 C NMR such as Figure 8 As shown in the figure, the values ​​of (101MHz, CDCl3) are: δ144.4 (dm, J = 247.3Hz), 140.8, 140.4 (dm, J = 263.2Hz), 138.2–137.6 (m), 133.9, 132.8, 127.9, 127.9, 126.8, 113.0–112.4 (m), 79.7, 62.0 (t, J = 3.8Hz), 28.8, 19.3.

[0086] Its nuclear magnetic resonance fluorine spectrum 19 F NMR such as Figure 9 As shown in the figure, (376MHz, CDCl3)δ-139.5–-139.7(m), -158.5–-158.7(m).

[0087] HRMS(ESI,m / z):calcd for C 20 H 20 F4NaO2 + [M+Na] +391.1292, found 391.1294.

[0088] Example 4

[0089] The fully substituted alkyl alkenyl ethers obtained in this invention can be introduced into bioactive molecules as intermediates. For example... Figure 10 As shown, the active molecule is an alcohol, which serves as a component reactant in the reaction of fully substituted alkyl alkenyl ethers, directly introducing the structure of the alkenyl ether into the active molecule.

[0090] In this invention, three reactants undergo a three-component coupling reaction to directly generate fully substituted alkenyl ethers. When an alkoxide is used alone as an additive, it acts as both a reactant and a base. When both an alcohol and an alkoxide are used as additives, the alcohol acts as a reactant while the alkoxide acts as a base. The preparation method is simple, efficient, and can selectively prepare fully substituted alkyl alkenyl ethers with defined configurations.

Claims

1. A method for preparing a per-substituted alkyl alkenyl ether, comprising the following steps: dissolving a catalyst, an additive, a 1-alkyne or a polyfluorobenzene and gem-difluorocyclopropane in a solvent, heating to a set temperature value, reacting sufficiently, and obtaining the desired per-substituted alkyl alkenyl ether after purification; the catalyst is chloro[1,3-bis(2,4,6-trimethylphenyl)imidazol-2-ylidene]copper(I); the additive is sodium tert-butoxide. The molar ratio of the catalyst to the gem-difluorocyclopropane is 0.00001-1:1; the molar ratio of the gem-difluorocyclopropane to the additive is 1:1-10; and the molar ratio of the gem-difluorocyclopropane to the 1-alkyne or the polyfluorobenzene is 1:1-10. The reaction temperature is 55-65 ℃, and the reaction time is 0.5-72 hours.

2. The method of claim 1, wherein the fully substituted alkyl alkenyl ether is prepared by the reaction of a fully substituted alkyl alkenyl halide with a fully substituted alkenyl alcohol. The 1-alkyne is octyne.

3. The method of claim 1, wherein the fully substituted alkyl alkenyl ether is prepared by the reaction of a fully substituted alkyl alkenyl halide with a fully substituted alkenyl alcohol in the presence of a base. 5 The polyfluorobenzene is 2,3,5,6-tetrafluoroanisole.

4. The method of claim 1, wherein the fully substituted alkyl alkenyl ether is prepared by the reaction of a fully substituted alkyl alkenyl halide with a fully substituted alkenyl alcohol in the presence of a base. ​ 5. The method of claim 1, wherein the fully substituted alkyl alkenyl ether is prepared by the reaction of a fully substituted alkyl alkenyl halide with a fully substituted alkenyl alcohol in the presence of a base. ​

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