CN114773229A - 1,6 diene compound and preparation method and application thereof - Google Patents

1,6 diene compound and preparation method and application thereof Download PDF

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CN114773229A
CN114773229A CN202210621116.1A CN202210621116A CN114773229A CN 114773229 A CN114773229 A CN 114773229A CN 202210621116 A CN202210621116 A CN 202210621116A CN 114773229 A CN114773229 A CN 114773229A
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解沛忠
张冬
高文秀
蔡昕颖
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Abstract

The invention discloses a 1,6 diene compound and a preparation method and application thereof. Stirring 0.01-0.25 mmol of palladium catalyst and 0.12-3 mmol of ligand for 1-6 h at normal temperature to obtain solution 1, adding solution 1, 0.2-5 mmol of allyl alcohol, 0.4-10 mmol of conjugated diene, 0.4-10 mmol of nucleophilic reagent, 0.02-0.5 mmol of calcium catalyst, 0.02-0.5 mmol of additive and 0.6-15 mmol of alkali into 2-50 mL of reaction solvent, and stirring for reaction for 12-24 h under the condition of inert gas atmosphere and 40-120 ℃ to obtain reaction liquid; removing the reaction solvent of the reaction solution, and purifying by thin layer chromatography/column chromatography to obtain the 1, 6-diene compound. The preparation method is green and mild, has low cost and high yield, and the obtained compound is an important skeleton widely existing in biological and pharmaceutical active molecules and has potential pharmaceutical activity and biological activity.

Description

1,6 diene compound and preparation method and application thereof
Technical Field
The invention belongs to the technical field of organic chemical synthesis, and particularly relates to a 1,6 diene compound and a preparation method and application thereof.
Background
The diene motif is one of the most important building blocks in organic chemistry, because it is ubiquitous in biologically relevant natural products, such as arachidonic acid, carotenoids, antibiotics, and marine natural products. In addition, dienes are valuable intermediates for the synthesis of various functions, such as the functionalization of carbocyclic and heterocyclic, cyclopropane or β -lactam olefins is an important class of reactions, the products containing pendant unsaturation, useful in downstream synthetic applications.
The existing synthesis method of 1, 6-diene compounds mainly uses transition metal catalysis and ligand to stabilize intermediate transition state by using high-reactivity allyl substrate and olefin with electron-withdrawing group, and has the main problems that:
(1) the allyl halide is used as an allyl electrophilic reagent, and the post-treatment of the generated by-product is complex and is not friendly to the environment;
(2) transition metal catalyzed three-component coupling, involving the oxidative addition of organic electrophiles to metals, in organic synthesis, inserting carbon-carbon multiple bonds, and then terminating with nucleophiles, but most of the nucleophiles employed are organometallic reagents such as organoborates, organosilanes, and organostannanes, which generate large amounts of metal salts and organic waste;
(3) enantioselective addition of allyl alcohol to unsaturated olefins is less common;
(4) the transition metal catalysts used are relatively expensive.
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 particularly to develop a method using allyl alcohol as a raw material and water as a byproduct.
Disclosure of Invention
In order to overcome the defects and shortcomings of the prior art, the invention aims to provide a preparation method of a 1,6 diene compound.
It is still another object of the present invention to provide the above 1,6 diene-based compound.
The invention also aims to provide application of the 1,6 diene compound.
The invention is realized by the following 1,6 diene compound, and the chemical structural formula of the compound is shown as the following formula (I):
Figure BDA0003674709300000021
in the formula (I), R1Any one selected from hydrogen radical, methyl or methoxy radical, nitrogen dimethyl, trifluoromethyl radical, fluoro radical, chloro radical, ferrocenyl radical, trimethyl silylethynyl radical, condensed aryl radical, heteroaryl radical, cycloalkyl radical and straight-chain alkyl radical;
R2any one selected from hydrogen radical, methyl or methoxy radical, tertiary butyl radical, nitrogen dimethyl, trifluoromethyl radical, fluoro radical, ferrocenyl radical, trimethyl silane ethynyl radical, chloro radical, condensed aryl radical, heteroaryl radical, cycloalkyl radical and straight-chain alkyl radical.
Preferably, the heteroaryl group is, for example, furan-2-yl or thiophen-2-yl; the cycloalkyl group is cyclohexyl.
The invention further discloses a preparation method of the 1,6 diene compound, which comprises the following steps:
(1) stirring 0.01-0.25 mmol of palladium catalyst and 0.12-3 mmol of ligand for 1-6 h at normal temperature to obtain solution 1, adding the solution 1, 0.2-5 mmol of allyl alcohol, 0.4-10 mmol of conjugated diene, 0.4-10 mmol of nucleophilic reagent, 0.02-0.5 mmol of calcium catalyst, 0.02-0.5 mmol of additive and 0.6-15 mmol of alkali into 2-50 mL of reaction solvent, and stirring for reaction under the conditions of inert gas atmosphere and 40-120 ℃;
(2) after TLC monitoring reaction is completed, removing reaction solvent of the reaction solution, and purifying by thin layer chromatography/column chromatography to obtain the 1, 6-diene compound.
Preferably, in step (1), the palladium catalyst is tetrakis (triphenylphosphine) palladium;
the ligand is any one of 1,1' -binaphthyl-2, 2' -bis-diphenylphosphine, 2- (di-tert-butylphosphine) biphenyl, 2- (dicyclohexylphosphine) -3, 6-dimethoxy-2 ' -4' -6' -tri-I-propyl-11 ' -biphenyl and 1,1' -bis (diphenylphosphine) ferrocene;
the allyl alcohol is selected from any one of Morita-Baylis-Hillman alcohol allyl alcohol, cinnamyl alcohol allyl alcohol and secondary allyl alcohol;
the conjugated diene is any one of 1, 3-diene, 1,3, 5-triene and chain olefin;
the nucleophilic reagent is selected from any one of malononitrile, 1, 3-cyclohexanedione and diethyl malonate;
the calcium catalyst is calcium bis (trifluoromethylsulfonyl imide);
the additive is selected from any one of sodium hexafluorophosphate, potassium hexafluorophosphate, ammonium hexafluorophosphate, tetraethylene hexafluorophosphate, tetrabutylammonium hexafluorophosphate, tetraethylene tetrafluoroborate, tetrabutylammonium tetrafluoroborate and potassium tetrafluoroborate;
the base is selected from any one of cesium carbonate, triethylamine, triethylene diamine, potassium tert-butoxide, 1, 5-diazabicyclo [4.3.0] -5-nonene, 1, 8-diazohetero-bis-spiro [5.4.0] undec-7-ene, cesium fluoride, 4-dimethylaminopyridine and N, N-diisopropylethylamine;
the reaction solvent is selected from any one of isopropanol, tetrahydrofuran, ethylene glycol dimethyl ether, toluene, ethanol and N, N-dimethylacetamide.
Preferably, in step (1), the allyl alcohol is selected from the group consisting of cinnamyl alcohol, p-methylcinnamyl alcohol, p-fluorocinnamyl alcohol, p-chlorocinnamyl alcohol, o-methoxycinnamyl alcohol, 1-phenyl-2-propen-1-ol, 1- (3-methoxyphenyl) prop-2-en-1-ol, 1-cyclohexylprop-2-en-1-ol, 1- (thien-2-yl) prop-2-en-1-ol, 1- (3-phenoxyphenyl) prop-2-en-1-ol, 2-methyl-1- (thien-2-yl) prop-2-en-1-ol, 1- (2-methoxyphenyl) prop-2-en-1-ol, p-methylcinnamyl alcohol, p-chlorocinnamyl alcohol, o-methoxycinnamyl alcohol, 1-phenyl-2-en-1-ol, 1- (2-methoxyphenyl) prop-2-en-1-ol, p-1-methoxy-2-1-phenyl-prop-2-ol, 1-2-ol, p-2-prop-1-ol, p-2-propenol, p-2-1-propenol, p-2-propenol, and, Any one of 1- (4- ((trimethylsilyl) ethynyl) phenyl) prop-2-en-1-ol.
Preferably, in the step (1), the conjugated diene is any one selected from 1, 3-butenyl benzene, 3- (m-methyl) -1, 3-butenyl benzene, 1,3, 5-trialkenyl benzene, 4- (p-methyl) phenyl butadiene, 4- (p-fluoro) phenyl butadiene, 4- (m-methyl) phenyl butadiene, 4- (o-methyl) phenyl butadiene, naphthyl butadiene, cyclohexyl butadiene, and 4-phenylhexatriene.
Preferably, in step (1), the ligand is 1,1 '-binaphthyl-2, 2' -bisdiphenylphosphine; the nucleophilic reagent is malononitrile; the additive is potassium hexafluorophosphate; the base is triethylene diamine; the solvent is isopropanol.
Preferably, in the step (1), the reaction is stirred under an argon gas atmosphere at 100 ℃.
Preferably, in step (2), the reaction solvent is removed by a vacuum rotary evaporator, and the developing solvent system is petroleum ether/ethyl acetate (mass ratio) 15/1.
The invention further discloses application of the 1,6 diene compound in preparing biologically and pharmaceutically active molecular frameworks.
The invention overcomes the defects of the prior art and provides a 1,6 diene compound and a preparation method and application thereof. The preparation method comprises the following steps:
(1) stirring a palladium catalyst and a ligand for 1-6 h at normal temperature to obtain a solution 1, sequentially adding the solution 1, allyl alcohol, conjugated diene, a nucleophilic reagent, a calcium catalyst, an additive and alkali into a reaction solvent, and stirring and reacting for 12-24 h under the condition of an inert gas atmosphere and at 40-120 ℃ to obtain a reaction solution.
For example, in one class of embodiments, the reaction equation is:
Figure BDA0003674709300000041
in the reaction scheme, compound 1 isAllyl alcohol, wherein R1Any one selected from hydrogen radical, methyl or methoxy radical, nitrogen dimethyl, trifluoromethyl radical, fluoro radical, chloro radical, ferrocenyl radical, trimethylsilylethynyl radical, condensed aryl radical, heteroaryl radical, cycloalkyl radical and straight-chain alkyl radical;
the compound 2 being a conjugated diene, R2Any one selected from hydrogen radical, methyl or methoxy radical, tertiary butyl radical, nitrogen dimethyl, trifluoromethyl radical, fluoro radical, ferrocenyl radical, trimethyl silyl ethynyl radical, chloro radical, condensed aryl radical, heteroaryl radical, cycloalkyl radical and straight-chain alkyl radical;
the compound 3 is a nucleophilic reagent, and the compound 4 is a product 1,6 diene compound.
(2) Removing the reaction solvent of the reaction solution, and purifying by thin layer chromatography/column chromatography to obtain the 1, 6-diene compound.
The method adopts a one-pot method to realize the cross-coupling reaction of three components, firstly, a nucleophilic reagent malononitrile generates malononitrile anion pairs under the action of alkali, then, the malononitrile anions carry out affinity attack on allyl ligands, diene and palladium are coordinated to form an intermediate, simultaneously, calcium activates C-O bonds, then, palladium is added by oxidation, the palladium is inserted into the terminal carbon of allyl alcohol, and then, the palladium reacts with the intermediate to obtain a target product. In the coupling reaction of three components catalyzed by transition metal, the control of regioselectivity and stereoselectivity and the inhibition of reactivity of competitive reaction are important factors to be considered. The malononitrile is used as a nucleophilic reagent, because the malononitrile is an important motif for synthesizing bioactive molecules, can be converted into other useful building blocks through reduction or hydrolysis, has unsaturated bonds in the synthesized product, is very favorable for subsequent modification work, and uses allyl alcohol as a reaction raw material, water is a unique byproduct, which is extremely environment-friendly.
Compared with the defects and shortcomings of the prior art, the invention has the following beneficial effects:
(1) part of the raw materials used in the preparation method of the invention are low-cost commercial cinnamyl alcohol raw materials, the applicable substrate range is wide, for example, allyl alcohol can be various substituted phenyl and alkyl, and the reaction is suitable for allyl alcohol and secondary allyl alcohol of different types, the other part is prepared from cinnamyl aldehyde, the preparation process is simple and convenient to operate, the yield is high, and the preparation cost is low; in addition, the preparation method has the characteristics of simple steps and convenience in operation, and the obtained by-product is only water and has the characteristics of environmental protection; the catalyst uses alkaline earth metal with low price and low toxicity, and has potential application value for fine chemistry and industrial production;
(2) the 1, 6-diene compound is an important skeleton widely existing in biological and pharmaceutical active molecules and has potential pharmaceutical activity and biological activity.
Drawings
FIG. 1 is a NMR chart of Compound 4 in example 1 of the present invention;
FIG. 2 is a NMR spectrum of Compound 4 in example 1 of the present invention;
FIG. 3 is a nuclear magnetic resonance hydrogen spectrum of Compound 8 in application example 3 of the present invention;
FIG. 4 is a nuclear magnetic resonance carbon spectrum of Compound 8 of practical example 3 of the present invention;
FIG. 5 is a NMR spectrum of Compound 10 of example 4 of the present invention;
FIG. 6 is a NMR carbon spectrum of Compound 10 of example 4 of the present invention.
FIG. 7 is a NMR spectrum of Compound 14 in example 6 of the present invention;
FIG. 8 is a NMR carbon spectrum of Compound 14 of example 6 of the present invention.
FIG. 9 is a NMR spectrum of Compound 16 in example 7 of the present invention;
FIG. 10 is a NMR carbon spectrum of Compound 16 of example 7 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 are not intended to limit the invention.
Example 1
(1) In a 10mL Schlenk tube, under nitrogen atmosphere, 0.01mmol of tetrakis (triphenylphosphine) palladium, 0.12mmol of 1,1 '-binaphthyl-2, 2' -bisdiphenylphosphine were added and stirred well for 3h at room temperature, and then 0.2mmol of cinnamyl alcohol, 0.4mmol of 1, 3-butenyl benzene, 0.4mmol of malononitrile, 0.6mmol of triethylene diamine, 0.02mmol of calcium bis (trifluoromethylsulfonyl) imide, 0.06mmol of potassium hexafluorophosphate, 2mL of isopropanol were added and stirred at 100 ℃ to react, wherein the reaction equation is:
Figure BDA0003674709300000061
(2) after the completion of the reaction was 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 (petroleum ether/ethyl acetate (mass ratio) 15/1) as a developing solvent, and was a pale yellow liquid compound 4 in 78% yield.
And (3) characterizing the compound 4, wherein the result is shown in figures 1-2, and the characterization result shows that the compound 4 is 2-cinnamyl-2- ((E) -4-phenylbut-3-en-2-yl) malononitrile.
Example 2
(1) In a 10mL Schlenk tube, under nitrogen atmosphere, 0.01mmol of tetrakis (triphenylphosphine) palladium, 0.12mmol of 1,1 '-binaphthyl-2, 2' -bisdiphenylphosphine were added and stirred well for 2h at room temperature, and then 0.2mmol of p-methylcinnamyl alcohol, 0.4mmol of 1, 3-butenylbenzene, 0.4mmol of malononitrile, 0.6mmol of triethylenediamine, 0.02mmol of calcium bis (trifluoromethylsulfonyl) imide, 0.06mmol of potassium hexafluorophosphate, 2mL of isopropanol were added and stirred at 100 ℃ for reaction, the reaction equation was:
Figure BDA0003674709300000071
(2) after the completion of the reaction was 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 (petroleum ether/ethyl acetate (mass ratio) 15/1) as a developing solvent and a pale yellow liquid compound 6 as a product in 73% yield.
Example 3
(1) In a 10mL Schlenk tube, under nitrogen atmosphere, 0.01mmol of tetrakis (triphenylphosphine) palladium, 0.12mmol of 1,1 '-binaphthyl-2, 2' -bisdiphenylphosphine are added and fully stirred at room temperature for 3h, then 0.2mmol of 1- (2-methoxyphenyl) prop-2-en-1-ol, 0.4mmol of 1, 3-butenylbenzene, 0.4mmol of malononitrile, 0.6mmol of triethylenediamine, 0.02mmol of calcium bis (trifluoromethylsulfonyl) imide and 0.02mmol of sodium hexafluorophosphate are added and stirred at 100 ℃ to react, and the reaction equation is as follows:
Figure BDA0003674709300000072
(2) after the completion of the reaction was 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 (petroleum ether/ethyl acetate (mass ratio) 15/1) as a developing solvent and was a pale yellow liquid compound 8 in 72% yield.
The compound 8 is characterized, and the result is shown in fig. 3-4, and the characterization result shows that the compound 8 is 2- ((E) -3- (2-methoxyphenyl) allyl) -2- ((E) -4-phenylbut-3-en-2-yl) malononitrile.
Example 4
(1) In a 10mL Schlenk tube, under nitrogen atmosphere, 0.01mmol of tetrakis (triphenylphosphine) palladium, 0.12mmol of 1,1 '-binaphthyl-2, 2' -bisdiphenylphosphine were added and stirred well for 3h at room temperature, and then 0.2mmol of cinnamyl alcohol, 0.4mmol of 4- (p-methyl) -1, 3-butenylbenzene, 0.4mmol of malononitrile, 0.6mmol of triethylene diamine, 0.02mmol of calcium bis (trifluoromethylsulfonyl) imide, 0.06mmol of potassium hexafluorophosphate, 2mL of isopropanol were added and stirred at 100 ℃ for reaction, the reaction equation was:
Figure BDA0003674709300000081
(2) after the completion of the reaction was 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 (petroleum ether/ethyl acetate (mass ratio) 15/1) as a developing solvent, and 10 was obtained as a pale yellow viscous liquid compound in 81% yield.
The compound 10 is characterized, and the result is shown in fig. 5-6, and the characterization result shows that the compound 10 is 2-cinnamyl-2- ((E) -4- (4-methyl) phenylbut-3-en-2-yl) malononitrile.
Example 5
(1) In a 10mL Schlenk tube, under nitrogen atmosphere, 0.01mmol of tetrakis (triphenylphosphine) palladium, 0.12mmol of 1,1 '-binaphthyl-2, 2' -bisdiphenylphosphine were added and stirred well for 3h at room temperature, and then 2mL of isopropanol, 0.2mmol of cinnamyl alcohol, 0.4mmol of 3- (m-methyl) -1, 3-butenylbenzene, 0.4mmol of malononitrile, 0.6mmol of triethylene diamine, 0.02mmol of calcium bis (trifluoromethylsulfonyl) imide, and 0.06mmol of potassium hexafluorophosphate were added and stirred at 100 ℃ for reaction, the reaction equation is:
Figure BDA0003674709300000091
(2) after the reaction was 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 (petroleum ether/ethyl acetate (mass ratio) 15/1) as a developing solvent, and was 12 as a pale yellow viscous liquid with a yield of 65%.
Example 6
(1) In a 10mL Schlenk tube, under nitrogen atmosphere, 0.01mmol of tetrakis (triphenylphosphine) palladium, 0.12mmol of 1,1 '-binaphthyl-2, 2' -bisdiphenylphosphine were added and stirred well for 3 hours at room temperature, and then 2mL of isopropanol, 0.2mmol of cinnamyl alcohol, 0.4mmol of 1,3, 5-trialkenylbenzene, 0.4mmol of malononitrile, 0.6mmol of triethylene diamine, 0.02mmol of calcium bis (trifluoromethylsulfonyl) imide, and 0.06mmol of potassium hexafluorophosphate were added and stirred at 100 ℃, the reaction equation is:
Figure BDA0003674709300000092
(2) after 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 (petroleum ether/ethyl acetate (mass ratio) ═ 15/1) as a developing solvent and a pale yellow viscous liquid 14 in 51% yield.
The compound 14 is characterized, and the result is shown in fig. 7-8, and the characterization result shows that the compound 14 is 2- [ (3E, 5E) -6-phenylhexa-3, 5-dien-2-yl ] -2- [ (2E) -3-phenyl-2-en-1-yl ] malononitrile.
Example 7
(1) In a 10mL Schlenk tube, under nitrogen atmosphere, 0.01mmol of tetrakis (triphenylphosphine) palladium, 0.12mmol of 1,1 '-binaphthyl-2, 2' -bisdiphenylphosphine were added and stirred well for 2h at room temperature, and then 0.2mmol of cinnamyl alcohol, 0.4mmol of 1, 3-octadiene, 0.4mmol of malononitrile, 0.6mmol of triethylene diamine, 0.02mmol of calcium bis (trifluoromethylsulfonyl) imide, 0.06mmol of potassium hexafluorophosphate, 2mL of isopropanol were added and stirred at 100 ℃ to react, wherein the reaction equation is:
Figure BDA0003674709300000101
(2) after 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 (petroleum ether/ethyl acetate (mass ratio) ═ 15/1) as the developing solvent and a pale yellow viscous liquid 16 as the product in 52% yield.
The compound 16 is characterized, and the result is shown in figures 9-10, and the characterization result shows that the compound 16 is 2- [ (3E) -non-3-en-2-yl ] -2- [ (2E) -3-phenyl-2-en-1-yl ] malononitrile.
Example 8
(1) In a 10mL schlenk tube, under the nitrogen environment, 0.25mmol of tetrakis (triphenylphosphine) palladium, 3mmol of 1,1 '-binaphthyl-2, 2' -bisdiphenylphosphine are added and fully stirred for 1h at room temperature, and then 5mmol of cinnamyl alcohol, 5mmol of 1, 4-diene, 10mmol of malononitrile, 15mmol of triethylene diamine, 0.5mmol of calcium bis (trifluoromethylsulfonyl) imide and 0.5mmol of potassium hexafluorophosphate are added and stirred for reaction at 40 ℃;
(2) after the reaction was monitored by TLC, the solvent was removed by a vacuum rotary evaporator, and the product was separated by thin layer chromatography using a petroleum ether/ethyl acetate system 15/1 as a developing solvent and 2-cinnamyl-2- ((E) -4-phenylbut-3-en-2-yl) malononitrile as a product at a yield of 72%.
Example 9
(1) In a 10mL Schlenk tube, under the nitrogen environment, 0.1mmol of tetrakis (triphenylphosphine) palladium and 0.2mmol of 1,1 '-binaphthyl-2, 2' -bisdiphenylphosphine are added and fully stirred for 6h at room temperature, and then 3mmol of cinnamyl alcohol, 5mmol of 1, 4-dialkene, 5mmol of malononitrile, 10mmol of triethylene diamine, 0.2mmol of calcium bis (trifluoromethylsulfonyl) imide and 0.3mmol of potassium hexafluorophosphate are added and stirred for reaction at 120 ℃;
(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 (15/1) as a developing solvent and 2-cinnamyl-2- ((E) -4-phenylbut-3-en-2-yl) malononitrile as a product in 65% yield.
Examples 10 to 15
Examples 10-15 are essentially the same as example 1, except as shown in table 1 below:
TABLE 1 Difference comparison
Figure BDA0003674709300000111
Application example 1
The present inventors have synthesized a macromolecular skeleton having a 1, 6-diene structure, based on the 1, 6-diene compound prepared in example 1 above, modified with estradiol, which is a potentially pharmaceutically and biologically active starting material.
The steps for modifying estradiol are as follows:
(1) adding (30-90) mmol of magnesium chloride and (30-90) mmol of triethylamine into (50-100) mL of tetrahydrofuran in which (10-30) mmol of estradiol and (50-150) mmol of paraformaldehyde are dissolved, putting the mixture into a sand bath kettle with magnetic stirring, refluxing the reaction for 12-24 hours, and monitoring the reaction by using a TLC plate, wherein the reaction equation is as follows:
Figure BDA0003674709300000112
(2) the mixture was transferred to a separatory funnel, extracted 3 times, and the aqueous layer was removed. After drying the organic layer over anhydrous magnesium sulfate, the organic layer was concentrated on a rotary evaporator and the residue was purified by column chromatography using petroleum ether and ethyl acetate (PE/EA) to yield the product 19 as a white solid.
(3) Adding (5-15) mmol 19, (50-150) mmol methyl iodide, (50-150) mmol potassium carbonate into (50-100) mL N, N-dimethylformamide, stirring at normal temperature for 12-24 hours, and monitoring the reaction by using a TLC plate, wherein the reaction equation is as follows:
Figure BDA0003674709300000121
(4) the mixture was transferred to a separatory funnel, extracted 3 times, and the aqueous layer was removed. After drying the organic layer over anhydrous magnesium sulfate, the organic layer was concentrated on a rotary evaporator and the residue was purified by column chromatography using petroleum ether and ethyl acetate (PE/EA) to give product 21 as a white solid.
(5) Adding (2-6) mmol 21 and (6-12) mmol vinyl magnesium bromide into (5-20) mL of ultra-dry tetrahydrofuran, transferring the mixed solution to the condition of-10 ℃, stirring for 2-3 hours, and monitoring the reaction by using a TLC plate, wherein the reaction equation is as follows:
Figure BDA0003674709300000122
(6) the mixture was transferred to a separatory funnel, extracted 3 times, and the aqueous layer was removed. After drying the organic layer over anhydrous magnesium sulfate, the organic layer was concentrated on a rotary evaporator and the residue was purified by column chromatography using petroleum ether and ethyl acetate (PE/EA) to yield the product 23 as an off-white solid.
(7) A150-mL round-bottom flask was charged with (5-15) mmol of vinyltriphenylphosphonium bromide, and the flask was purged with nitrogen. Then adding 30-80 ml of ultra-dry tetrahydrofuran in a nitrogen environment at zero centigrade, then adding (5-15) mmol of n-butyllithium, and stirring for 1-4 h at zero centigrade to fully react; and (5-15) mmol of 21 is added at zero DEG C, and the mixture is moved to room temperature and stirred for more than 6 hours to fully react. The reaction was monitored using TLC plates; after the reaction is finished, the reaction solution is quenched by using saturated ammonium chloride solution. The mixture was transferred to a separatory funnel and extracted with dichloromethane and water, and the organic layer was dried over anhydrous sodium sulfate. After drying, the obtained organic layer was concentrated by a vacuum evaporator, and finally purified by column chromatography using an developed system of petroleum ether and ethyl acetate to obtain the target product 26 as a white solid. The reaction equation is
Figure BDA0003674709300000131
(7) This example is the same as example 3 above, with the equation:
Figure BDA0003674709300000132
(8) after the reaction was 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 as a developing solvent in the form of a white solid 27 at 58% yield.
(9) This example is the same as example 4 above, with the equation:
Figure BDA0003674709300000133
(10) 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 as the developing solvent in 28% as a white solid with a yield of 40%.
Application example 2
The macromolecular skeleton with allylamine structure can be synthesized by modifying zidovudine which has potential pharmaceutical activity and biological activity as a raw material. The method comprises the following steps:
(1) after 29 was obtained in the same manner as in example 3, 0.2mmol of 27 was dissolved in 3mL of ultra-dry tetrahydrofuran under an air atmosphere, the reaction was cooled to completion at 0 ℃ and 0.4mmol of tetrabutylammonium fluoride and 10mmol of water were slowly added dropwise. The reaction is carried out for 2-4 h at 0 ℃, a TLC plate is used for monitoring the reaction, and the reaction equation is as follows:
Figure BDA0003674709300000141
(2) after 31 was obtained in the same manner as in example 4, 0.2mmol of 31 was dissolved in 3mL of ultra-dry tetrahydrofuran under an air atmosphere, the reaction was cooled completely at 0 ℃ and 0.4mmol of tetrabutylammonium fluoride and 10mmol of water were slowly added dropwise. The reaction is carried out for 2-4 h at 0 ℃, and a TLC plate is used for monitoring the reaction, wherein the reaction equation is as follows:
Figure BDA0003674709300000142
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 yellow liquid 30, 32, yield is 87%, 85% respectively.
(3) Adding 0.2mmol 30, 0.22mmol zidovudine, 0.1mmol copper sulfate pentahydrate, 0.2mmol sodium ascorbate, 2mL tertiary butanol and 2mL water in a 10mL Schlenk tube under the argon environment, stirring and reacting for 20h at normal temperature, wherein the reaction equation is as follows:
Figure BDA0003674709300000143
(4) in a 10mL Schlenk tube, under the argon atmosphere, adding 0.2mmol, 0.22mmol of zidovudine, 0.1mmol of copper sulfate pentahydrate, 0.2mmol of sodium ascorbate, 2mL of tert-butyl alcohol and 2mL of water, stirring and reacting for 20h at normal temperature, wherein the reaction equation is as follows:
Figure BDA0003674709300000151
the mixture was transferred to a separatory funnel, extracted 3 times, and the aqueous layer was removed. After drying the organic layer over anhydrous magnesium sulfate, the organic layer was concentrated on a rotary evaporator and the residue was purified by column chromatography using ethanol and dichloromethane (EtOH/DCM) as white solid products 34, 35 in 83%, 84% yields, respectively.
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. A1, 6 diene compound, characterized in that the chemical structural formula of the compound is shown as the following formula (I):
Figure FDA0003674709290000011
in the formula (I), R1Any one selected from hydrogen radical, methyl or methoxy radical, nitrogen dimethyl, trifluoromethyl radical, fluoro radical, chloro radical, ferrocenyl radical, trimethyl silylethynyl radical, condensed aryl radical, heteroaryl radical, cycloalkyl radical and straight-chain alkyl radical;
R2any one selected from hydrogen radical, methyl or methoxy radical, tertiary butyl radical, nitrogen dimethyl, trifluoromethyl radical, fluoro radical, ferrocenyl radical, trimethyl silane ethynyl radical, chloro radical, condensed aryl radical, heteroaryl radical, cycloalkyl radical and straight-chain alkyl radical.
2. The 1,6 diene compound according to claim 1 wherein the heteroaryl group is, for example, furan-2-yl or thiophen-2-yl; the cycloalkyl group is cyclohexyl.
3. A process for the preparation of a 1,6 diene compound according to claim 1 or 2, characterized in that it comprises the following steps:
(1) stirring 0.01-0.25 mmol of palladium catalyst and 0.12-3 mmol of ligand for 1-6 h at normal temperature to obtain solution 1, adding the solution 1, 0.2-5 mmol of allyl alcohol, 0.4-10 mmol of conjugated diene, 0.4-10 mmol of nucleophilic reagent, 0.02-0.5 mmol of calcium catalyst, 0.02-0.5 mmol of additive and 0.6-15 mmol of alkali into 2-50 mL of reaction solvent, and stirring for reaction under the conditions of inert gas atmosphere and 40-120 ℃;
(2) after TLC monitoring reaction is completed, removing reaction solvent of reaction liquor, then utilizing thin layer chromatography/column chromatography to make purification so as to obtain 1, 6-diene compound.
4. The process for producing a 1,6 diene compound according to claim 3, wherein in the step (1),
the palladium catalyst is tetrakis (triphenylphosphine) palladium;
the ligand is selected from any one of 1,1' -binaphthyl-2, 2' -bis-diphenylphosphine, 2- (di-tert-butylphosphine) biphenyl, 2- (dicyclohexylphosphine) -3, 6-dimethoxy-2 ' -4' -6' -tri-I-propyl-11 ' -biphenyl and 1,1' -bis (diphenylphosphine) ferrocene;
the allyl alcohol is selected from any one of Morita-Baylis-Hillman alcohol allyl alcohol, cinnamyl alcohol allyl alcohol and secondary allyl alcohol;
the conjugated diene is any one of 1, 3-diene, 1,3, 5-triene and chain olefin;
the nucleophilic reagent is selected from any one of malononitrile, 1, 3-cyclohexanedione and diethyl malonate;
the calcium catalyst is calcium bis (trifluoromethylsulfonyl imide);
the additive is selected from any one of sodium hexafluorophosphate, potassium hexafluorophosphate, ammonium hexafluorophosphate, tetraethylene phosphate, tetrabutyl ammonium hexafluorophosphate, tetraethylene amine tetrafluoroborate, tetrabutyl ammonium tetrafluoroborate and potassium tetrafluoroborate;
the alkali is selected from any one of cesium carbonate, triethylamine, triethylene diamine, potassium tert-butoxide, 1, 5-diazabicyclo [4.3.0] -5-nonene, 1, 8-diazohetero-bis-spiro [5.4.0] undec-7-ene, cesium fluoride, 4-dimethylaminopyridine and N, N-diisopropylethylamine;
the reaction solvent is any one of isopropanol, tetrahydrofuran, ethylene glycol dimethyl ether, toluene, ethanol and N, N-dimethylacetamide.
5. The method according to claim 4, wherein in the step (1), the allyl alcohol is selected from the group consisting of cinnamyl alcohol, p-methylcinnamyl alcohol, p-fluorocinnamyl alcohol, p-chlorocinnamyl alcohol, o-methoxycinnamyl alcohol, 1-phenyl-2-propen-1-ol, 1- (3-methoxyphenyl) prop-2-en-1-ol, 1-cyclohexylprop-2-en-1-ol, 1- (thien-2-yl) prop-2-en-1-ol, 1- (3-phenoxyphenyl) prop-2-en-1-ol, 2-methyl-1- (thien-2-yl) prop-2-en-1-ol, 1- (2-methoxyphenyl) prop-2-en-1-ol, 1- (4- ((trimethylsilyl) ethynyl) phenyl) prop-2-en-1-ol.
6. The method according to claim 4, wherein in the step (1), the conjugated diene is any one selected from the group consisting of 1, 3-butenylbenzene, 3- (m-methyl) -1, 3-butenylbenzene, 1,3, 5-trialkenylbenzene, 4- (p-methyl) phenylbutadiene, 4- (p-fluoro) phenylbutadiene, 4- (m-methyl) phenylbutadiene, 4- (o-methyl) phenylbutadiene, naphthylbutadiene, cyclohexylbutadiene, and 4-phenylhexatriene.
7. The method according to claim 4, wherein in step (1), the ligand is 1,1 '-binaphthyl-2, 2' -bis-diphenylphosphine; the nucleophilic reagent is malononitrile; the additive is potassium hexafluorophosphate; the base is triethylene diamine; the solvent is isopropanol.
8. The preparation method according to claim 3, wherein in the step (1), the reaction solution is obtained by stirring and reacting for 12 to 24 hours under an argon gas atmosphere at 100 ℃.
9. The method of claim 3, wherein in step (2), the reaction solvent is removed by a vacuum rotary evaporator, and the developing solvent system is petroleum ether/ethyl acetate 15/1.
10. Use of a 1,6 diene compound according to claim 1 or claim 2 for the preparation of a biologically and pharmaceutically active molecular scaffold.
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Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
ADAMSON, NATHAN J.等: "Enantioselective Intermolecular Pd-Catalyzed Hydroalkylation of Acyclic 1,3-Dienes with Activated Pronucleophiles", JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, vol. 140, no. 8, pages 2761 - 2764 *
MAN-BO LI等: "Catalytic stereospecific alkylation of malononitriles with enantioenriched primary allylic amines†", CHEM. COMMUN., vol. 49, pages 8190 - 8192, XP055780626, DOI: 10.1039/c3cc44914a *

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