CN115322100A - Delta, epsilon-alkenyl ketone compound and preparation method and application thereof - Google Patents
Delta, epsilon-alkenyl ketone compound and preparation method and application thereof Download PDFInfo
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- C07C69/73—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of unsaturated acids
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- C07C67/333—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton
- C07C67/343—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
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Abstract
The invention discloses a delta, epsilon-alkenyl ketone compound and a preparation method and application thereof. Under the inert gas atmosphere, adding 0.02-0.8 mmol of catalyst, 0.04-1.6 mmol of ligand, 0.01-0.4 mmol of dimethylamine aqueous solution and 0.2-8 mmol of water into a reaction solvent, stirring for 1-4 h, adding 0.4-16 mmol of cyclopropane and 0.2-8 mmol of allyl alcohol, and stirring and reacting for 12-48 h at 50-100 ℃; removing the reaction solvent of the reaction solution, and purifying by thin layer chromatography/column chromatography to obtain the delta, epsilon-alkenyl ketone compound. The preparation method has the characteristics of low preparation cost, simple steps, convenient operation, high product yield, environmental protection and the like, and the obtained compound can be used as an organic synthesis building block to perform various derivatizations by utilizing the alkenyl and carbonyl parts. In addition, the delta, epsilon-alkenyl ketone motif is also an important skeleton widely existing in natural products, biological and drug molecules, and has potential biological activity and pharmaceutical activity.
Description
Technical Field
The invention belongs to the technical field of organic chemical synthesis, and particularly relates to a delta, epsilon-alkenyl ketone compound, and a preparation method and application thereof.
Background
Delta, epsilon-alkenyl ketones and their derivatives are commonly found in many natural products, bioactive molecules and drug molecules, such as Zearalenone (Zearalenone) which is a growth promoter with estrogenic activity and can be used as a veterinary drug; alcyonolide isolated from Ceriporia tangutica sp is cytotoxic to HCT 116 cells; methylamine fumarate (methyl fumarate) is a novel aminoalkyl substituted benzoheterocyclic compound, and has bactericidal and anti-cholesterol activity; the drug molecules Sirolimus (Sirolimus) and Everolimus (Everolimus) with delta, epsilon-alkenyl ketone functional motif are mainly used as a potent immunosuppressant to slow down rejection reaction after organ transplantation operation and treat cancer. In addition, δ, ∈ -alkenyl ketones having two different active sites of alkenyl and carbonyl groups can be used as valuable organic synthesis intermediates to undergo a series of functional reactions such as hydrogenation reduction, michael addition, and cyclization, and therefore, development of synthetic methods for δ, ∈ -alkenyl ketones compounds has attracted considerable attention in the organic synthesis community.
Transition metals promote or catalyze allylation reactions, which are one of the most important tools for building carbon-carbon bonds in organic synthesis. In previous work, allylation of cyclopropanol has mostly been performed using metal catalyzed cyclopropanol and allyl reagents with good leaving groups, such as allyl halides, allyl methanesulfonates, allyl phosphates or allyl carbonates, but the preparation and reaction of such allyl reagents inevitably produces stoichiometric salt waste, whereas allyl alcohol itself was originally not considered due to its known weak leaving group-the presence of the hydroxyl group.
Most of the ring-opening allylation reactions of the cyclopropanol use expensive catalysts, which greatly limits the industrial application. Therefore, from an environmental and economic point of view, it is very attractive to develop an energy-saving and efficient green synthesis method using nontoxic, inexpensive, readily available and relatively harmless raw materials and catalysts, and particularly to a method using allyl alcohol as a raw material and water as a byproduct. This method is complementary to other reactions, such as the conjugate addition of an allyl nucleophile or the enolization of a homoallyl electrophile.
Disclosure of Invention
In order to overcome the defects and shortcomings of the prior art, the invention mainly aims to provide a preparation method of delta, epsilon-alkenyl ketone compounds.
The invention also aims to provide a delta, epsilon-alkenyl ketone compound.
The invention also aims to provide application of the delta, epsilon-alkenyl ketone compound.
The invention is realized by a delta, epsilon-alkenyl ketone compound, the chemical structural formula of which is shown as the following formula (I):
in the formula (I), R 1 Any one selected from hydrogen radical, methyl, methoxy, cyano, nitro, tert-butyl, azoxydimethyl, trifluoromethyl, fluoro, chloro, bromo, ferrocenyl, trimethylsilylethynyl, fused aryl, heteroaryl, cycloalkyl and straight-chain alkyl;
R 2 any one selected from hydrogen radical, methyl, methoxy, cyano, nitro, tert-butyl, azoxydimethyl, trifluoromethyl, fluoro, bromo, chloro, ferrocenyl, trimethylsilylethynyl, fused aryl, heteroaryl, cycloalkyl and straight-chain alkyl.
Preferably, the heteroaryl group is, for example, furyl or thienyl; the cycloalkyl group is cyclohexyl.
The invention further discloses a preparation method of the delta, epsilon-alkenyl ketone compound, which comprises the following steps:
(1) Under the inert gas atmosphere, adding 0.02-0.8 mmol of catalyst, 0.04-1.6 mmol of ligand, 0.01-0.4 mmol of dimethylamine aqueous solution and 0.2-8 mmol of water into a reaction solvent, stirring for 1-4 h, adding 0.4-16 mmol of cyclopropyl alcohol and 0.2-8 mmol of allyl alcohol, and stirring and reacting for 12-48 h at 50-100 ℃; wherein, the first and the second end of the pipe are connected with each other,
the catalyst is selected from any one of cuprous chloride, cuprous bromide, cuprous iodide, a complex of copper trifluoromethanesulfonate and benzene, cuprous thiophene-2-formate, copper tetraacetonitrile hexafluorophosphate, copper tetraacetonitrile tetrafluoroborate and copper acetate;
the ligand is selected from any one of 4, 5-bisdiphenylphosphine-9, 9-dimethylxanthene, dicyclohexyl [3, 6-dimethoxy-2 ',4',6 '-triisopropyl [1,1' -biphenyl ] -2-yl ] phosphine, 1, 2-bis (diphenylphosphine) ethane, tris (4-methoxyphenyl) phosphine, 2-dicyclohexylphosphine-2 ',4',6 '-triisopropylbiphenyl, 2- (di-tert-butylphosphine) biphenyl, 1, 3-dimethyl-2-imidazolidinone, (S, S) - (-) -2,2' -isopropylidenebis (4-tert-butyl-2-oxazoline), 8-amino-5-bromoquinoline, 1, 3-dimethyluracil, 2-iodopyridine, 2-cyanopyrimidine, 2, 4-dichloro-5-iodopyrimidine, 2-chloropyrimidine, 1, 10-phenanthroline, 4 '-bipyridine, 5-fluorouracil, 2,4, 6-tribromopyrimidine, uracil, N-acetylcytosine, 2' -bipyridine, 4-di-tert-butyl-2-bipyridine, alpha-terpyridine;
the reaction solvent is selected from any one of tetrahydrofuran, ethylene glycol dimethyl ether, toluene, dimethyl sulfoxide, acetone, N-dimethylformamide and N, N-dimethylacetamide;
the cyclopropanol is selected from any one of aryl cyclopropanol, heteroaryl cyclopropanol and alkyl cyclopropanol;
the allyl alcohol is allyl alcohol with an electron withdrawing group at the beta position;
(2) And (3) after TLC monitoring reaction is completed, removing the solvent from the reaction liquid obtained in the step (1), and purifying to obtain the delta, epsilon-alkenyl ketone compound.
Preferably, in step (1), the cyclopropanol is selected from the group consisting of 1- (thien-3-yl) cyclopropane-1-ol, 1- (furan-2-yl) cyclopropane-1-ol, 1-benzylcyclopropane-1-ol, 1- (4-fluorobenzyl) cyclopropane-1-ol, 1- (4-bromobenzyl) cyclopropane-1-ol, 1- (4-chlorobenzyl) cyclopropane-1-ol, 1- (4-methylbenzyl) cyclopropane-1-ol, 1- (4- (tert-butyl) benzyl) cyclopropane-1-ol, 1- (4-methoxybenzyl) cyclopropane-1-ol, 1- ((diphenyl) methyl) cyclopropane-1-ol, 1- (1-phenylpropyl) cyclopropane-1-ol, 1- (phenoxymethyl) cyclopropane-1-ol, 1- (cyclohex-1-en-1-ylmethyl) cyclopropane-1-ol, 1- (cyclohexylmethyl) cyclopropane-1-ol, 1-phenylethylcyclopropane-1-ol, 1- (4-methoxyethyl) cyclopropane-1-ol, 1- (bromophenyl) cyclopropane-1-ol, 1- (3-bromophenylethyl) cyclopropane-1-ol, 1- (2- (2-phenyl-1, 3-dioxolan-2-yl) ethyl) cyclopropane-1-ol, 1-phenylpropylcyclopropane-1-ol, 1-isopropylcyclopropane-1-ol, 1- (2, 2-diethoxyethyl) cyclopropane-1-ol, 1-pentylcyclopropane-1-ol, 1- (8- (oxiran-2-yl) octyl) cyclopropane-1-ol.
Preferably, in step (1), the allyl alcohol is selected from any one of methyl 2-hydroxy (phenyl) methacrylate, methyl 2-hydroxy (4-fluorobenzene) methacrylate, methyl 2-hydroxy (4-trifluoromethylbenzene) methacrylate, methyl 2-hydroxy (4-nitrobenzene) methacrylate, methyl 2-hydroxy (4-oxycarbonylbenzene) methacrylate, methyl 2-hydroxy (4-methoxybenzene) methacrylate, methyl 2-hydroxy (4-tert-butylbenzene) methacrylate, methyl 2-hydroxy (3-fluorobenzene) methacrylate, methyl 2-hydroxy (2-chlorobenzene) methacrylate, methyl 2-hydroxy (3, 5-dimethylbenzene) methacrylate, methyl 2-hydroxy (naphthalen-1-yl) methacrylate, methyl 2-hydroxy (pyridin-3-yl) methacrylate, methyl 2-hydroxy (thiophen-2-yl) methacrylate, ethyl 2-hydroxy (phenyl) methacrylate, tert-butyl 2-hydroxy (phenyl) methacrylate, menthyl 2-hydroxy- (2, 4-yl) methacrylate, 2-hydroxy- (2, 4-dichlorophenyl) methacrylate, and bis (4-hydroxy) acetone methacrylate.
Preferably, in step (1), the catalyst is copper tetraacetonitrilhexafluorophosphate; the ligand is uracil; the solvent is N, N-dimethylformamide.
Preferably, in step (1), the reaction is stirred at 60 ℃ for 24h.
Preferably, in the step (2), the solvent removal is vacuum rotary evaporator solvent removal, the purification is purification by thin layer chromatography/column chromatography, and the developing solvent system is petroleum ether/ethyl acetate =5/1.
The invention further discloses application of the delta, epsilon-alkenyl ketone compound in the synthesis of a macromolecular skeleton compound with a delta, epsilon-alkenyl ketone structure by modifying natural products.
Preferably, the natural product comprises menthol, diacetone galactose, cholesterol.
The invention overcomes the defects of the prior art and provides a delta, epsilon-alkenyl ketone compound and a preparation method and application thereof. The preparation method comprises the following steps:
(1) Adding a catalyst, a ligand, a dimethylamine aqueous solution and water into a reaction solvent, stirring for 1-4 h, adding cyclopropanol and allyl alcohol, and stirring to react for 12-48 h under the inert gas atmosphere and at the temperature of 50-100 ℃ to obtain a reaction solution;
for example, in one class of embodiments, the reaction equation is:
in the reaction scheme, compound 1 is a cyclopropanol, wherein R 1 Any one selected from hydrogen radical, methyl or methoxy radical, cyano radical, nitro radical, tertiary butyl radical, nitrogen dimethyl, trifluoromethyl radical, fluoro radical, chloro radical, bromo radical, ferrocenyl radical, trimethylsilylethynyl radical, condensed aryl radical, heteroaryl radical, cycloalkyl radical and straight-chain alkyl radical;
compound 2 is allyl alcohol, R 2 Any one selected from hydrogen radical, methyl or methoxy radical, cyano radical, nitro radical, tertiary butyl radical, nitrogen dimethyl, trifluoromethyl radical, fluoro radical, ferrocenyl radical, trimethylsilylethynyl radical, chloro radical, bromo radical, condensed aryl radical, heteroaryl radical, cycloalkyl radical and straight-chain alkyl radical;
compound 3 is the product delta, epsilon-alkenyl ketone compound.
(2) And (2) removing the reaction solvent of the reaction liquid obtained in the step (1), and purifying by thin layer chromatography/column chromatography to obtain the delta, epsilon-alkenyl ketone compound.
The method directly uses allyl alcohol to replace a pre-prepared activated allyl reagent as an olefin source, selects the ring opening of the cyclopropanol to introduce carbonyl fragments, and generates a product and only byproduct water under the catalysis of cheap copper salt which is not easy to carry out beta-H elimination reaction, thereby leading the reaction to occur in an environment-friendly way under mild conditions.
Compared with the defects and shortcomings of the prior art, the invention has the following beneficial effects:
(1) The allyl alcohol used in the preparation method is the allyl alcohol with the electron withdrawing group at the beta position, which has simple synthesis and high conversion rate, and the applicable substrate range is wide, for example, the allyl alcohol can be various substituted phenyl and alkyl groups, and the preparation method has the characteristic of low preparation cost; in addition, the preparation method has the advantages of simple steps, convenient operation and high product yield, and the obtained byproduct is only water, so the method has the characteristics of high atom economy and environmental protection; in addition, the catalyst used in the preparation method is a copper catalyst which is cheap and easy to obtain, and has potential application value for fine chemistry and industrial production;
(2) The delta, epsilon-alkenyl ketone compound can be used as an organic synthesis building block for carrying out various derivatizations by utilizing the alkenyl and carbonyl parts, is also an important skeleton widely existing in natural products, organisms and drug molecules, and has potential biological activity and drug activity.
Drawings
FIG. 1 is a NMR spectrum of Compound 3 in example 1 of the present invention;
FIG. 2 is a nuclear magnetic resonance carbon spectrum of Compound 3 in example 1 of the present invention;
FIG. 3 is a NMR spectrum of Compound 5 in example 2 of the present invention;
FIG. 4 is a NMR carbon spectrum of Compound 5 of example 2 of the present invention;
FIG. 5 is a NMR spectrum of Compound 7 in example 3 of the present invention;
FIG. 6 is a NMR carbon spectrum of Compound 7 of example 3 of the present invention;
Detailed Description
In order to make the objects, technical solutions and advantages of the present invention more apparent, the present invention is described in further detail below with reference to the accompanying drawings and embodiments. It should be understood that the specific embodiments described herein are merely illustrative of the invention and do not limit the invention.
Example 1
(1) In a 10mL Schlenk tube, under nitrogen atmosphere, 0.05mmol of copper tetraacetonitrile hexafluorophosphate, 0.1mmol of uracil, 0.014mmol of aqueous dimethylamine solution and 0.8mmol of water are added to 2mL of N, N-dimethylformamide, and after stirring well for 1h, 0.6mmol of 1-phenethylcyclopropane-1-ol and 0.2mmol of methyl 2-hydroxy (phenyl) methacrylate are added, and the mixture is stirred and reacted at 60 ℃ for 24h, wherein the reaction equation is as follows:
(2) After TLC monitoring reaction is completed, vacuum rotary evaporator is used to remove solvent, thin layer chromatography is used to separate product, developing agent is petroleum ether/ethyl acetate system (5/1), product is colorless transparent liquid compound 3, yield is 80%.
The compound 3 is characterized, and the result is shown in figures 1-2, and the characterization result shows that the compound 3 is (E) -2-benzylidene-6-oxo-8-phenyloctanoic acid methyl ester.
Example 2
(1) In a 10mL Schlenk tube, under nitrogen atmosphere, 0.02mmol of copper tetraacetonitrile hexafluorophosphate, 0.04mmol of uracil, 0.014mmol of aqueous dimethylamine solution and 0.8mmol of water are added to 2mL of N, N-dimethylformamide, and after fully stirring for 4 hours, 0.4mmol of 1-phenethylcyclopropane-1-ol and 0.2mmol of 2-hydroxy (4-methylbenzene) methyl methacrylate are added, and the mixture is stirred and reacted at 60 ℃ for 48 hours, wherein the reaction equation is as follows:
(2) After TLC monitoring reaction is completed, vacuum rotary evaporator is used to remove solvent, thin layer chromatography is used to separate product, developing agent is petroleum ether/ethyl acetate system (5/1), product is light yellow liquid compound 5, yield is 78%.
The compound 5 is characterized, and the results are shown in figures 3-4, and the characterization result shows that the compound 5 is (E) -2- (4-methylbenzylidene) -6-oxo-8-phenyloctanoic acid methyl ester.
Example 3
(1) In a 10mL Schlenk tube, under nitrogen atmosphere, 0.02mmol of copper tetraacetonitrile hexafluorophosphate, 0.04mmol of uracil, 0.014mmol of aqueous dimethylamine solution and 0.4mmol of water are added to 2mL of N, N-dimethylformamide, and after stirring thoroughly for 2h, 0.4mmol of 1-phenethylcyclopropane-1-ol and 0.2mmol of 2-hydroxy (4-methoxybenzene) methyl methacrylate are added, and the mixture is stirred and reacted at 60 ℃ for 20h, wherein the reaction equation is as follows:
(2) After TLC monitoring reaction is completed, vacuum rotary evaporator is used to remove solvent, thin layer chromatography is used to separate product, developing agent is petroleum ether/ethyl acetate system (5/1), product is light yellow liquid compound 7, yield is 96%.
The compound 7 is characterized, and the results are shown in FIGS. 5 to 6, and the characterization result shows that the compound 7 is (E) -2- (4-methoxybenzylidene) -6-oxo-8-phenyloctanoic acid methyl ester.
Example 4
(1) In a 10mL Schlenk tube, under nitrogen atmosphere, 0.02mmol of copper tetraacetonitrile hexafluorophosphate, 0.04mmol of uracil, 0.014mmol of aqueous dimethylamine solution and 0.8mmol of water were added to 2mL of N, N-dimethylformamide, and after stirring well for 3 hours, 0.4mmol of 1-benzylcyclopropane-1-ol and 0.2mmol of methyl 2-hydroxy (phenyl) methacrylate were added, and the mixture was stirred at 60 ℃ for 20 hours, the reaction equation is:
(2) After TLC monitoring reaction is completed, vacuum rotary evaporator is used to remove solvent, thin layer chromatography is used to separate product, developing agent is petroleum ether/ethyl acetate system (5/1), product is light yellow liquid compound 9, yield is 65%.
Example 5
(1) In a 10mL Schlenk tube, under a nitrogen atmosphere, 0.02mmol of copper tetraacetonitrile hexafluorophosphate, 0.04mmol of uracil, 0.015mmol of aqueous dimethylamine solution and 1.2mmol of water are added to 2mL of N, N-dimethylformamide, after stirring well for 2h, 0.4mmol of 1- (4-bromophenylethyl) cyclopropane-1-ol and 0.2mmol of methyl 2-hydroxy (phenyl) methacrylate are added, and the mixture is stirred and reacted at 60 ℃ for 12h, wherein the reaction equation is as follows:
(2) After the completion of the reaction monitored by TLC, the solvent was removed by a vacuum rotary evaporator and the product was isolated by thin layer chromatography using a petroleum ether/ethyl acetate system (5/1) as a developing solvent in the form of a white solid compound 11 in 64% yield.
Example 6
This example 6 is substantially the same as example 1, except that in step (1): in a 250mL Schlenk tube, 0.8mmol of copper tetraacetonitrile hexafluorophosphate, 1.6mmol of uracil, 0.4mmol of an aqueous dimethylamine solution and 8mmol of water were added to 80mL of N, N-dimethylformamide under a nitrogen atmosphere, and after stirring thoroughly for 1 hour, 169mol of 1-phenethylcyclopropane-1-ol and 8mmol of 2-hydroxy (phenyl) methyl methacrylate were added, and the mixture was stirred at 60 ℃ for reaction for 24 hours.
Example 7
This example 7 is substantially the same as example 1, except that in step (1): in a 25mL Schlenk tube, 0.02mmol of copper tetraacetonitrile hexafluorophosphate, 0.04mmol of uracil, 0.01mmol of aqueous dimethylamine solution and 0.8mmol of water were added to 6mL of N, N-dimethylformamide under a nitrogen atmosphere, and after stirring well for 3 hours, 0.4mmol of 1-phenethylcyclopropane-1-ol and 0.2mmol of 2-hydroxy (phenyl) methyl methacrylate were added, and the reaction was stirred at 60 ℃ for 24 hours.
Examples 8 to 15
Examples 8-15 are essentially the same as example 2, with the differences shown in table 1 below:
TABLE 1 Difference comparison
Application example 1
The delta, epsilon-alkenyl ketone compound prepared in example 1 was modified with menthol, a natural product having potential pharmaceutical and biological activities, to synthesize a macromolecular skeleton having a delta, epsilon-alkenyl ketone structure.
The modification procedure for menthol is as follows:
(1) Under the protection of nitrogen and at room temperature, 24mmol of menthol is added into a dichloromethane solution, 40mmol of triethylamine is added at 0 ℃, and the mixture is stirred for 0.5h. Then 20mmol of acryloyl chloride in dichloromethane is dripped into the reaction liquid at the temperature of 0 ℃, and the reaction mixture is obtained after stirring reaction for 12 hours at room temperature. The reaction equation is:
(2) The reaction mixture was quenched with saturated ammonium chloride solution, extracted 3 times with ether, the organic phases were combined, dried over anhydrous magnesium sulfate, the solvent was removed under reduced pressure, and the product was isolated by column chromatography on silica gel using a petroleum ether/ethyl acetate system as developing solvent in a colorless liquid 14, yield 93%.
(3) Under the protection of nitrogen and at room temperature, 20mmol of 2, 4-dichlorobenzaldehyde, 24mmol of 14 and 10mmol of triethylene diamine are dissolved in tetrahydrofuran, and the mixture is stirred at room temperature for 1 week to obtain a reaction mixture. The reaction equation is:
(4) The reaction mixture was subjected to column silica gel chromatography to isolate the product as a colorless liquid 16, using a petroleum ether/ethyl acetate system as a developing solvent, in 89% yield.
(5) This example is essentially the same as example 2 above, except that allyl alcohol is 16 obtained as described above, the reaction equation being:
(6) After the TLC monitoring reaction is completed, the solvent is removed by a vacuum rotary evaporator, and the product is separated by thin layer chromatography, the developing agent is a petroleum ether/ethyl acetate system, the product is light yellow liquid 17, and the yield is 81%.
Application example 2
The macromolecular skeleton with delta, epsilon-alkenyl ketone structure can be synthesized by using a natural product diacetone galactose with potential pharmaceutical activity and biological activity for modification.
The modification steps of diacetone galactose are as follows:
(1) Under the protection of nitrogen and at room temperature, 24mmol of diacetone galactose is added into a dichloromethane solution, 40mmol triethylamine is added at 0 ℃, and the mixture is stirred for 0.5h. Then 20mmol of acryloyl chloride in dichloromethane is dripped into the reaction liquid at the temperature of 0 ℃, and the reaction mixture is obtained after stirring reaction for 12 hours at room temperature. The reaction equation is:
(2) The reaction mixture was quenched with saturated ammonium chloride solution, extracted 3 times with ether, the organic phases were combined, dried over anhydrous magnesium sulfate, the solvent was removed under reduced pressure, and the product was isolated by column silica gel chromatography using a petroleum ether/ethyl acetate system as the developing solvent to give 19 as a white solid in 95% yield.
(3) Under the protection of nitrogen and at room temperature, 20mmol of 2, 4-dichlorobenzaldehyde, 24mmol of 19 and 10mmol of triethylene diamine are dissolved in tetrahydrofuran, and the mixture is stirred at room temperature for 1 week to obtain a reaction mixture. The reaction equation is as follows:
(4) The reaction mixture was freed of the solvent under reduced pressure and the product was isolated by column chromatography on silica gel with a developer of petroleum ether/ethyl acetate system to give 20% as a white solid in 94% yield.
(5) This example is essentially the same as example 2 above, except that allyl alcohol is 20 obtained as described above, the reaction equation is:
(6) After TLC monitoring reaction is completed, vacuum rotary evaporator is used to remove solvent, thin layer chromatography is used to separate product, developing agent is petroleum ether/ethyl acetate system, product is light yellow liquid 21, yield is 97%.
Application example 3
The macromolecular skeleton with delta, epsilon-alkenyl ketone structure can be synthesized by modifying natural product cholesterol with potential pharmaceutical activity and biological activity.
The cholesterol modification steps are as follows:
(1) Under the protection of nitrogen and at room temperature, 24mmol of cholesterol is added into a dichloromethane solution, 40mmol of triethylamine is added at 0 ℃, and the mixture is stirred for 0.5h. And then 20mmol of acryloyl chloride in dichloromethane is dripped into the reaction liquid at the temperature of 0 ℃, and the reaction mixture is obtained after stirring reaction for 12 hours at room temperature. The reaction equation is:
(2) The reaction mixture was quenched by addition of saturated ammonium chloride solution, extracted 3 times with ether, the organic phases were combined, dried over anhydrous magnesium sulfate, the solvent was removed under reduced pressure, and the product was isolated by column chromatography on silica gel using a petroleum ether/ethyl acetate system as developing solvent in the form of a white solid 23% yield of 61%.
(3) Under the protection of nitrogen and at room temperature, 20mmol of 2, 4-dichlorobenzaldehyde, 24mmol of 23 and 10mmol of triethylene diamine are dissolved in tetrahydrofuran, and the mixture is stirred at room temperature for 1 week to obtain a reaction mixture. The reaction equation is:
(4) The reaction mixture was chromatographed on column silica gel using a petroleum ether/ethyl acetate system as the developing agent in 58% yield as a white solid 24.
(5) This example is essentially the same as example 2 above, except that allyl alcohol is 24 obtained as described above, the reaction equation being:
(6) After TLC monitoring reaction is completed, vacuum rotary evaporator is used to remove solvent, thin layer chromatography is used to separate product, developing agent is petroleum ether/ethyl acetate system, product is light yellow liquid 25, yield is 65%.
The above description is only for the purpose of illustrating the preferred embodiments of the present invention and is not to be construed as limiting the invention, and any modifications, equivalents and improvements made within the spirit and principle of the present invention are intended to be included within the scope of the present invention.
Claims (10)
1. A δ, ε -alkenyl ketone compound, wherein the chemical formula of the compound is shown as following formula (I):
in the formula (I), R 1 Any one selected from hydrogen radical, methyl, methoxy, cyano, nitro, tert-butyl, azoxydimethyl, trifluoromethyl, fluoro, chloro, bromo, ferrocenyl, trimethylsilylethynyl, fused aryl, heteroaryl, cycloalkyl and straight-chain alkyl;
R 2 selected from hydrogen radicals,Any one of methyl, methoxy, cyano, nitro, tert-butyl, azoxydimethyl, trifluoromethyl, fluoro, bromo, chloro, ferrocenyl, trimethylsilylethynyl, fused aryl, heteroaryl, cycloalkyl and straight-chain alkyl.
2. The δ, ε -alkenyl ketones of claim 1, wherein said heteroaryl is such as furyl or thienyl; the cycloalkyl group is cyclohexyl.
3. A preparation method of delta, epsilon-alkenyl ketone compounds is characterized by comprising the following steps:
(1) Under the inert gas atmosphere, adding 0.02-0.8 mmol of catalyst, 0.04-1.6 mmol of ligand, 0.01-0.4 mmol of dimethylamine aqueous solution and 0.2-8 mmol of water into a reaction solvent, stirring for 1-4 h, adding 0.4-16 mmol of cyclopropane and 0.2-8 mmol of allyl alcohol, and stirring and reacting for 12-48 h at 50-100 ℃; wherein, the first and the second end of the pipe are connected with each other,
the catalyst is selected from any one of cuprous chloride, cuprous bromide, cuprous iodide, a complex of copper trifluoromethanesulfonate and benzene, cuprous thiophene-2-formate, copper tetraacetonitrile hexafluorophosphate, copper tetraacetonitrile tetrafluoroborate and copper acetate;
the ligand is selected from any one of 4, 5-bisdiphenylphosphine-9, 9-dimethylxanthene, dicyclohexyl [3, 6-dimethoxy-2 ',4',6 '-triisopropyl [1,1' -biphenyl ] -2-yl ] phosphine, 1, 2-bis (diphenylphosphine) ethane, tris (4-methoxyphenyl) phosphine, 2-dicyclohexylphosphine-2 ',4',6 '-triisopropylbiphenyl, 2- (di-tert-butylphosphine) biphenyl, 1, 3-dimethyl-2-imidazolidinone, (S, S) - (-) -2,2' -isopropylidenebis (4-tert-butyl-2-oxazoline), 8-amino-5-bromoquinoline, 1, 3-dimethyluracil, 2-iodopyridine, 2-cyanopyrimidine, 2, 4-dichloro-5-iodopyrimidine, 2-chloropyrimidine, 1, 10-phenanthroline, 4 '-bipyridine, 5-fluorouracil, 2,4, 6-tribromopyrimidine, uracil, N-acetylcytosine, 2' -bipyridine, 4-di-tert-butyl-2-bipyridine, alpha-terpyridine;
the reaction solvent is selected from any one of tetrahydrofuran, ethylene glycol dimethyl ether, toluene, dimethyl sulfoxide, acetone, N-dimethylformamide and N, N-dimethylacetamide;
the cyclopropanol is selected from any one of aryl cyclopropanol, heteroaryl cyclopropanol and alkyl cyclopropanol;
the allyl alcohol is allyl alcohol with an electron withdrawing group at the beta position;
(2) And (3) after TLC monitoring reaction is completed, removing the solvent from the reaction liquid obtained in the step (1), and purifying to obtain the delta, epsilon-alkenyl ketone compound.
4. The production method according to claim 3, wherein in step (1), the cyclopropane is selected from the group consisting of 1- (thien-3-yl) cyclopropane-1-ol, 1- (furan-2-yl) cyclopropane-1-ol, 1-benzylcyclopropane-1-ol, 1- (4-fluorobenzyl) cyclopropane-1-ol, 1- (4-bromobenzyl) cyclopropane-1-ol, 1- (4-chlorobenzyl) cyclopropane-1-ol, 1- (4-methylbenzyl) cyclopropane-1-ol, 1- (4- (tert-butyl) benzyl) cyclopropane-1-ol, 1- (4-methoxybenzyl) cyclopropane-1-ol, 1- ((diphenyl) methyl) cyclopropane-1-ol, 1- (1-phenylpropyl) cyclopropane-1-ol, 1- (phenoxymethyl) cyclopropane-1-ol, 1- (cyclohex-1-en-1-ylmethyl) cyclopropane-1-ol, 1- (cyclohexylmethyl) cyclopropane-1-ylethyl) cyclopropane-1-ol, 1- (1-methoxyethyl) cyclopropane-1-yl) cyclopropane-ol, 1- (bromomethyl) cyclopropane-1-yl) cyclopropane-1-ol, 1- (cyclohexylmethyl) cyclopropane-1-ethyl) cyclopropane-ol, 1-ethyl (1-yl) cyclopropane-ethyl) cyclopropane-1-yl) benzene ethyl (bromobenzyl) alcohol, and the like, 1- (3-bromophenylethyl) cyclopropane-1-ol, 1- (2- (2-phenyl-1, 3-dioxolan-2-yl) ethyl) cyclopropane-1-ol, 1-phenylpropylcyclopropane-1-ol, 1-isopropylcyclopropane-1-ol, 1- (2, 2-diethoxyethyl) cyclopropane-1-ol, 1-pentylcyclopropane-1-ol, 1- (8- (oxiran-2-yl) octyl) cyclopropane-1-ol.
5. The production method according to claim 3, wherein, in the step (1), the allyl alcohol is selected from the group consisting of methyl 2-hydroxy (phenyl) methacrylate, methyl 2-hydroxy (4-fluorophenyl) methacrylate, methyl 2-hydroxy (4-trifluoromethylbenzene) methacrylate, methyl 2-hydroxy (4-nitrophenyl) methacrylate, methyl 2-hydroxy (4-oxycarbonylphenyl) methacrylate, methyl 2-hydroxy (4-methoxybenzene) methacrylate, methyl 2-hydroxy (4-tert-butylbenzene) methacrylate, methyl 2-hydroxy (3-fluorophenyl) methacrylate, methyl 2-hydroxy (2-chlorobenzene) methacrylate, methyl 2-hydroxy (3, 5-dimethylbenzene) methacrylate, methyl 2-hydroxy (naphthalen-1-yl) methacrylate, methyl 2-hydroxy (pyridin-3-yl) methacrylate, methyl 2-hydroxy (thiophen-2-yl) methacrylate, ethyl 2-hydroxy (phenyl) methacrylate, tert-butyl 2-hydroxy (phenyl) methacrylate, menthyl 2-hydroxy- (2, 4-dichlorophenyl) methacrylate, 2-hydroxy- (2, 4-cholesteryl) methacrylate, bis (4-dichlorophenyl) methacrylate, and optionally galacto-propanoate of 2-hydroxy (4-dichlorophenyl) methacrylate, 2, 4-hydroxy (4-dichlorophenyl) methacrylate, bis (galactosyl) acrylate One kind of the medicine.
6. The method according to claim 3, wherein in the step (1), the catalyst is tetraacetonitrileconpper hexafluorophosphate; the ligand is uracil; the solvent is N, N-dimethylformamide.
7. The method according to claim 3, wherein in the step (1), the reaction is stirred at 60 ℃ for 24 hours.
8. The method of claim 3, wherein in the step (2), the solvent removal is a vacuum rotary evaporator to remove the reaction solvent, the purification is a purification by thin layer chromatography/column chromatography, and the developing solvent system is petroleum ether/ethyl acetate =5/1.
9. Use of the δ, ε -alkenyl ketone compounds of claim 1 or 2 in the modification of natural products to synthesize macromolecular backbone compounds with δ, ε -alkenyl ketone structure.
10. The use of claim 9, wherein the natural product comprises menthol, galactose diacetone, cholesterol.
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| CN117185966A (en) * | 2023-09-18 | 2023-12-08 | 安徽金桐精细化学有限公司 | Method for carrying out open-loop sulfonylation on cycloalkanol |
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