CN114773229B - 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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CN114773229B
CN114773229B CN202210621116.1A CN202210621116A CN114773229B CN 114773229 B CN114773229 B CN 114773229B CN 202210621116 A CN202210621116 A CN 202210621116A CN 114773229 B CN114773229 B CN 114773229B
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解沛忠
张冬
高文秀
蔡昕颖
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Nanjing Tech University
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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 1, 0.2-5 mmol of allyl alcohol, 0.4-10 mmol of conjugated diene, 0.4-10 mmol of nucleophile, 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 and reacting for 12-24 h under the condition of 40-120 ℃ in an inert gas atmosphere to obtain reaction solution; removing the reaction solvent of the reaction liquid, and purifying by thin layer chromatography/column chromatography to obtain the 1, 6-diene compound. The preparation method of the invention is green, mild, low in cost and high in benefit, 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 a1, 6 diene compound, and a preparation method and application thereof.
Background
Dienyl moiety 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 carbocycles and heterocycles, functionalization of cyclopropane or β -lactam olefins is an important class of reactions, and products containing pendant unsaturation are useful for downstream synthesis applications.
The existing synthesis method of 1, 6-diene compounds mainly uses a high-reactivity allyl substrate and olefin with electron withdrawing groups, uses transition metal catalysis and ligand to stabilize intermediate transition states, and has the main problems that:
(1) The allyl halide is adopted as the allyl electrophile, and the generated byproducts are complex in post-treatment and not friendly to the environment;
(2) Transition metal catalyzed three-component coupling involves the oxidative addition of an organic electrophile to a metal, in an organic synthesis, intercalating carbon-carbon multiple bonds and then terminating with a nucleophile, but most of the nucleophiles employed are organometallic reagents such as organoborates, organosilanes and organotin alkanes, which can produce 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.
Thus, from an environmental and economic standpoint, it is extremely attractive to develop an energy efficient green synthesis process using non-toxic, inexpensive, readily available and relatively environmentally benign raw materials, particularly a process that uses allyl alcohol directly as a raw material and water as a byproduct.
Disclosure of Invention
In order to overcome the defects and shortcomings in the prior art, the primary purpose of the invention is to provide a preparation method of 1,6 diene compounds.
It is still another object of the present invention to provide the above 1, 6-diene compound.
It is another object of the present invention to provide the use of the above 1,6 diene-based compounds.
The invention is realized in such a way that a1, 6 diene compound has a chemical structural formula shown in the following formula (I):
In the formula (I), R 1 is selected from any one of hydrogen, methyl or methoxy, azomethine, trifluoromethyl, fluoro, chloro, ferrocenyl, trimethylsilanylethynyl, condensed aryl, heteroaryl, cycloalkyl and directly-connected alkyl;
R 2 is selected from any one of hydrogen, methyl or methoxy, tertiary butyl, azomethine, trifluoromethyl, fluoro, ferrocenyl, trimethylsilane ethynyl, chloro, condensed aryl, heteroaryl, cycloalkyl and directly connected alkyl.
Preferably, the heteroaryl is, for example, furan-2-yl or thiophen-2-yl; the cycloalkyl 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 1, 0.2-5 mmol of allyl alcohol, 0.4-10 mmol of conjugated diene, 0.4-10 mmol of nucleophile, 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 condition of inert gas atmosphere and 40-120 ℃;
(2) After the TLC monitoring reaction is completed, the reaction solvent of the reaction solution is removed, and then the reaction solution is purified by a thin layer chromatography/column chromatography method to obtain the 1, 6-diene compound.
Preferably, in step (1), the palladium catalyst is tetrakis (triphenylphosphine) palladium;
The ligand is selected from any one of 1,1' -binaphthyl-2, 2' -diphenyl phosphine, 2- (di-tert-butyl phosphine) biphenyl, 2- (dicyclohexylphosphine) -3, 6-dimethoxy-2 ' -4' -6' -tri-I-propyl-11 ' -biphenyl and 1,1' -bis (diphenyl phosphine) ferrocene;
The allyl alcohol is selected from MoritA-Baylis-Hillman alcohol allyl alcohol, cinnamyl alcohol allyl alcohol or secondary allyl alcohol;
the conjugated diene is selected from 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 bis (trifluoromethylsulfonyl imide) calcium;
the additive is selected from any one of sodium hexafluorophosphate, potassium hexafluorophosphate, ammonium hexafluorophosphate, tetraethylammonium hexafluorophosphate, tetrabutylammonium hexafluorophosphate, tetraethylammonium 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-diazabicyclo [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 any one 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- (thiophen-2-yl) prop-2-en-1-ol, 1- (3-phenoxyphenyl) prop-2-en-1-ol, 2-methyl-1- (thiophen-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.
Preferably, in the step (1), the conjugated diene is selected from any one of 1, 3-butenyl benzene, 3- (m-methyl) -1, 3-butenyl benzene, 1,3,5, -trialkenyl benzene, 4- (p-methyl) phenylbutadiene, 4- (p-fluoro) phenylbutadiene, 4- (m-methyl) phenylbutadiene, 4- (o-methyl) phenylbutadiene, naphthylbutadiene, cyclohexylbutadiene, 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 alkali is triethylene diamine; the solvent is isopropanol.
Preferably, in step (1), the reaction is stirred under an argon 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 preparation of bioactive and pharmaceutical active molecular frameworks.
The invention overcomes the defects of the prior art and provides a1, 6 diene compound and a preparation method and application thereof. The preparation method of the invention comprises the following steps:
(1) The palladium catalyst and the ligand are stirred for 1 to 6 hours at normal temperature to obtain a solution 1, the solution 1, allyl alcohol, conjugated diene, nucleophilic reagent, calcium catalyst, additive and alkali are sequentially added into a reaction solvent, and the mixture is stirred and reacted for 12 to 24 hours under the condition of inert gas atmosphere and 40 to 120 ℃ to obtain a reaction solution.
Taking one kind of implementation as an example, the chemical equation of the reaction is:
In the reaction formula, the compound 1 is allyl alcohol, wherein R 1 is any one of hydrogen, methyl or methoxy, azomethine, trifluoromethyl, fluoro, chloro, ferrocenyl, trimethylsilane ethynyl, condensed aryl, heteroaryl, cycloalkyl and directly connected alkyl;
compound 2 is a conjugated diene, R 2 is any one selected from the group consisting of hydrogen, methyl or methoxy, t-butyl, azadimethyl, trifluoromethyl, fluoro, ferrocenyl, trimethylsilanylethynyl, chloro, fused aryl, heteroaryl, cycloalkyl, and direct alkyl;
compound 3 is nucleophilic reagent and compound 4 is product 1,6 diene compound.
(2) Removing the reaction solvent of the reaction liquid, and purifying by thin layer chromatography/column chromatography to obtain the 1, 6-diene compound.
According to the invention, a one-pot method is adopted to realize cross coupling reaction of three components, firstly, a nucleophilic reagent malononitrile generates malononitrile anion pair under the action of alkali, then the malononitrile anion carries out affinity attack on an allyl ligand, diene coordinates with palladium to form an intermediate, meanwhile, calcium activates a C-O bond, then palladium is added through oxidation, palladium is inserted into terminal carbon of allyl alcohol, and then the intermediate reacts 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 the reactivity of competing reactions are important factors to be considered, in the invention, a one-pot method is adopted to selectively construct carbon-carbon bonds for the three components, and the selective functionalization of the same two C-H bonds is realized under a double-catalysis system of palladium and calcium. Malononitrile is used as a nucleophile, because malononitrile is an important motif for synthesizing bioactive molecules, and can be converted into other useful building blocks by reduction or hydrolysis, and the synthesized product has unsaturated bonds, which is also very advantageous for subsequent modification work, and allyl alcohol is used as a reaction raw material, and water is the only byproduct, which is clearly very friendly to the environment.
Compared with the defects and shortcomings of the prior art, the invention has the following beneficial effects:
(1) The preparation method has the characteristics that one part of raw materials used in the preparation method is low-cost commercial cinnamyl alcohol raw materials, the applicable substrate range is wide, for example, allyl alcohol can be various substituted phenyl groups and alkyl groups, the reaction is applicable to different types of allyl alcohol and secondary allyl alcohol, and the other part of the raw materials is prepared from cinnamyl aldehyde, so that 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, convenient operation, and the obtained byproducts are only water, so that the preparation method has the characteristics of environmental protection; the catalyst is 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 framework widely existing in biological and pharmaceutical active molecules, and has potential pharmaceutical activity and biological activity.
Drawings
FIG. 1 is a nuclear magnetic resonance hydrogen spectrum of compound 4 in example 1 of the present invention;
FIG. 2 is a nuclear magnetic resonance carbon 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 in application example 3 of the present invention;
FIG. 5 is a nuclear magnetic resonance hydrogen spectrum of compound 10 in example 4 of the present invention;
FIG. 6 is a nuclear magnetic resonance carbon spectrum of compound 10 in example 4 of the present invention.
FIG. 7 is a nuclear magnetic resonance hydrogen spectrum of compound 14 in example 6 of the present invention;
FIG. 8 is a nuclear magnetic resonance carbon spectrum of compound 14 in example 6 of the present invention.
FIG. 9 is a nuclear magnetic resonance hydrogen spectrum of compound 16 in example 7 of the present invention;
FIG. 10 is a nuclear magnetic resonance carbon spectrum of compound 16 in example 7 of the present invention.
Detailed Description
The present invention will be described in further detail with reference to the drawings and examples, in order to make the objects, technical solutions and advantages of the present invention more apparent. It should be understood that the specific embodiments described herein are for purposes of illustration only and are not intended to limit the scope of the invention.
Example 1
(1) In a 10mL Schlenk tube, 0.01mmol of tetrakis (triphenylphosphine) palladium, 0.12mmol of 1,1 '-binaphthyl-2, 2' -bisdiphenylphosphine are added under nitrogen atmosphere, and stirred fully for 3h at room temperature, then 0.2mmol of cinnamyl alcohol, 0.4mmol of 1, 3-butenyl benzene, 0.4mmol of malononitrile, 0.6mmol of triethylenediamine, 0.02mmol of bis (trifluoromethylsulfonyl) imide calcium and 0.06mmol of potassium hexafluorophosphate are added, and 2mL of isopropanol are added, and stirred and reacted at 100 ℃ to obtain the following reaction equation:
(2) After the reaction was completed by TLC, the solvent was removed by vacuum rotary evaporator, and the product was isolated by thin layer chromatography as a petroleum ether/ethyl acetate system (petroleum ether/ethyl acetate (mass ratio) =15/1) as a pale yellow liquid compound 4 in 78% yield.
The characterization of the compound 4 is shown in fig. 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, 0.01mmol of tetrakis (triphenylphosphine) palladium, 0.12mmol of 1,1 '-binaphthyl-2, 2' -bisdiphenylphosphine are added under nitrogen atmosphere, and stirred fully for 2h at room temperature, then 0.2mmol of p-methyl cinnamyl alcohol, 0.4mmol of 1, 3-butenyl benzene, 0.4mmol of malononitrile, 0.6mmol of triethylenediamine, 0.02mmol of bis (trifluoromethylsulfonyl) imide calcium and 0.06mmol of potassium hexafluorophosphate are added, and 2mL of isopropanol is added, and the reaction is stirred at 100 ℃ to obtain the following reaction equation:
(2) After the reaction was completed by TLC, the solvent was removed by vacuum rotary evaporator, and the product was isolated by thin layer chromatography as a petroleum ether/ethyl acetate system (petroleum ether/ethyl acetate (mass ratio) =15/1) as a pale yellow liquid compound 6 in 73% yield.
Example 3
(1) In a 10mL Schlenk tube, 0.01mmol of tetrakis (triphenylphosphine) palladium, 0.12mmol of 1,1 '-binaphthyl-2, 2' -bisdiphenylphosphine, 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 bis (trifluoromethylsulfonyl) imide calcium and 0.02mmol of sodium hexafluorophosphate are added under nitrogen, and the mixture is stirred for 3h at room temperature, and then the reaction equation is:
(2) After the reaction was completed by TLC, the solvent was removed by vacuum rotary evaporator, and the product was isolated by thin layer chromatography as a petroleum ether/ethyl acetate system (petroleum ether/ethyl acetate (mass ratio) =15/1) as a pale yellow liquid compound 8 in a yield of 72%.
The characterization of compound 8 is shown in fig. 3-4, and the characterization result shows that 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, 0.01mmol of tetrakis (triphenylphosphine) palladium, 0.12mmol of 1,1 '-binaphthyl-2, 2' -bisdiphenylphosphine, 0.2mmol of cinnamyl alcohol, 0.4mmol of 4- (p-methyl) -1, 3-butenyl benzene, 0.4mmol of malononitrile, 0.6mmol of triethylenediamine, 0.02mmol of bis (trifluoromethylsulfonyl) imide calcium and 0.06mmol of potassium hexafluorophosphate are added under nitrogen, and 2mL of isopropanol are added and stirred at 100 ℃ to react:
(2) After the reaction was completed by TLC, the solvent was removed by vacuum rotary evaporator, and the product was isolated by thin layer chromatography as a petroleum ether/ethyl acetate system (petroleum ether/ethyl acetate (mass ratio) =15/1) as a pale yellow viscous liquid compound 10 in 81% yield.
The characterization of compound 10 is shown in fig. 5-6, which shows that compound 10 is 2-cinnamyl-2- ((E) -4- (4-methyl) phenylbut-3-en-2-yl) malononitrile.
Example 5
(1) In a 10mL Schlenk tube, 0.01mmol of tetrakis (triphenylphosphine) palladium, 0.12mmol of 1,1 '-binaphthyl-2, 2' -bisdiphenylphosphine, 0.2mmol of cinnamyl alcohol, 0.4mmol of 3- (m-methyl) -1, 3-butenyl benzene, 0.4mmol of malononitrile, 0.6mmol of triethylenediamine, 0.02mmol of bis (trifluoromethylsulfonyl) imide calcium and 0.06mmol of potassium hexafluorophosphate are added under nitrogen, and 2mL of isopropanol are added and stirred at 100 ℃ to react:
(2) After the reaction was completed by TLC, the solvent was removed by vacuum rotary evaporator, and the product was isolated by thin layer chromatography as a petroleum ether/ethyl acetate system (petroleum ether/ethyl acetate (mass ratio) =15/1) as a pale yellow viscous liquid 12 in 65% yield.
Example 6
(1) In a10 mL Schlenk tube, 0.01mmol of tetrakis (triphenylphosphine) palladium, 0.12mmol of 1,1 '-binaphthyl-2, 2' -bisdiphenylphosphine are added under nitrogen, and the mixture is fully stirred for 3 hours at room temperature, then 0.2mmol of cinnamyl alcohol, 0.4mmol of 1,3, 5-trialkenylbenzene, 0.4mmol of malononitrile, 0.6mmol of triethylenediamine, 0.02mmol of bis (trifluoromethylsulfonyl) imide calcium and 0.06mmol of potassium hexafluorophosphate are added, and 2mL of isopropanol are added, and the mixture is stirred at 100 ℃ to react with the following reaction equation:
(2) After the reaction was completed by TLC, the solvent was removed by vacuum rotary evaporator, and the product was isolated by thin layer chromatography as a petroleum ether/ethyl acetate system (petroleum ether/ethyl acetate (mass ratio) =15/1) as a pale yellow viscous liquid 14 in a yield of 51%.
The characterization of compound 14 is shown in fig. 7-8, which shows that 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, 0.01mmol of tetrakis (triphenylphosphine) palladium, 0.12mmol of 1,1 '-binaphthyl-2, 2' -bisdiphenylphosphine are added under nitrogen atmosphere, and stirred fully for 2h at room temperature, then 0.2mmol of cinnamyl alcohol, 0.4mmol of 1, 3-octadiene, 0.4mmol of malononitrile, 0.6mmol of triethylenediamine, 0.02mmol of bis (trifluoromethylsulfonyl) imide calcium and 0.06mmol of potassium hexafluorophosphate are added, and 2mL of isopropanol are added for stirring reaction at 100 ℃, wherein the reaction equation is as follows:
(2) After the reaction was completed by TLC, the solvent was removed by vacuum rotary evaporator, and the product was isolated by thin layer chromatography as a petroleum ether/ethyl acetate system (petroleum ether/ethyl acetate (mass ratio) =15/1) as a pale yellow viscous liquid 16 in a yield of 52%.
The characterization of compound 16 is shown in fig. 9-10, which shows that 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 atmosphere, 0.25mmol of tetra (triphenylphosphine) palladium and 3mmol of 1,1 '-binaphthyl-2, 2' -bisdiphenylphosphine are firstly added, and the mixture is fully stirred for 1h at room temperature, and then 5mmol of cinnamyl alcohol, 5mmol of 1, 4-diene, 10mmol of malononitrile, 15mmol of triethylenediamine, 0.5mmol of bis (trifluoromethylsulfonyl) imide calcium and 0.5mmol of potassium hexafluorophosphate are added, and 50mL of isopropanol is added, and the mixture is stirred for reaction at 40 ℃;
(2) After the completion of the reaction, the solvent was removed by vacuum rotary evaporator, and the product was isolated by thin layer chromatography as petroleum ether/ethyl acetate system=15/1, 2-cinnamyl-2- ((E) -4-phenylbut-3-en-2-yl) malononitrile as a product in 72% yield.
Example 9
(1) In a 10mL Schlenk tube, under the nitrogen atmosphere, 0.1mmol of tetra (triphenylphosphine) palladium and 0.2mmol of 1,1 '-binaphthyl-2, 2' -bisdiphenylphosphine are firstly added, fully stirred for 6 hours at room temperature, 3mmol of cinnamyl alcohol, 5mmol of 1, 4-diene, 5mmol of malononitrile, 10mmol of triethylene diamine, 0.2mmol of bis (trifluoromethylsulfonyl) imide calcium and 0.3mmol of potassium hexafluorophosphate are added, and 30mL of isopropanol is added, and stirred for reaction at 120 ℃;
(2) After the completion of the reaction, the solvent was removed by vacuum rotary evaporator, and the product was isolated by thin layer chromatography with 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 to 15 are substantially the same as example 1, except that the following table 1 shows:
Table 1 differential comparison
Application example 1
According to the present invention, the 1, 6-diene compound prepared in example 1 above was modified with estradiol as a potentially pharmaceutically and biologically active material to synthesize a macromolecular scaffold having a1, 6-diene structure.
The modification steps of the estradiol are as follows:
(1) Adding (30-90) mmol of magnesium chloride and (30-90) mmol of triethylamine into (50-100) mL of tetrahydrofuran for dissolving (10-30) mmol of estradiol and (50-150) mmol of paraformaldehyde, placing into a sand bath pot with magnetic stirring, and carrying out reaction reflux for 12-24 hours, wherein a TLC plate is used for monitoring the reaction, and the reaction equation is as follows:
(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 give 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:
(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, (6-12) mmol vinyl magnesium bromide into (5-20) mL ultra-dry tetrahydrofuran, transferring the mixed solution to the condition of minus 10 ℃, stirring for 2-3 hours, monitoring the reaction by using a TLC plate, wherein the reaction equation is as follows:
(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 give the product as an off-white solid product 23.
(7) To a 150ml round bottom flask was added (5-15) mmol of vinyl triphenylphosphine bromide, and the flask was purged with nitrogen. Then adding 30-80 ml of ultra-dry tetrahydrofuran in a nitrogen environment at zero ℃, then adding (5-15) mmol of n-butyllithium, and stirring for 1-4 hours at zero ℃ to fully react; then adding (5-15) mmol 21 at zero degree centigrade, moving to room temperature, stirring for more than 6 hours to make it fully react. The reaction was monitored using TLC plates; after the completion of the reaction, the reaction solution was quenched with saturated ammonium chloride solution. The mixture was transferred to a separating funnel, 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 a developed system of petroleum ether and ethyl acetate to obtain the target product 26 as a white solid. The reaction equation is
(7) This example is the same as example 3 above, with the reaction equation:
(8) After the completion of the reaction, TLC was followed by removal of the solvent by vacuum rotary evaporator, and the product was isolated by thin layer chromatography as a petroleum ether/ethyl acetate system as a white solid 27 in 58% yield.
(9) This example is identical to example 4 above, and the reaction equation is:
(10) After the completion of the reaction, TLC was followed by removal of the solvent by vacuum rotary evaporator, and the product was isolated by thin layer chromatography as a petroleum ether/ethyl acetate system as a white solid 28 in 40% yield.
Application example 2
The macromolecular skeleton with allylamine structure can be synthesized by modifying the raw material zidovudine with potential pharmaceutical activity and biological activity. 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 in an air atmosphere, and the reaction mixture was cooled completely at 0℃to slowly add 0.4mmol of tetrabutylammonium fluoride and 10mmol of water. The reaction was carried out at 0℃for 2-4 h, monitored by TLC plates, and the reaction equation was:
(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 in an air atmosphere, and the reaction mixture was cooled completely at 0℃to slowly add 0.4mmol of tetrabutylammonium fluoride and 10mmol of water. The reaction was carried out at 0℃for 2-4 h, monitored by TLC plates, and the reaction equation was:
After the completion of the reaction, TLC was followed by removal of the solvent by vacuum rotary evaporator, separation of the product by thin layer chromatography with the developing solvent being petroleum ether/ethyl acetate system and the products being yellow liquids 30, 32 in 87% and 85% yields, respectively.
(3) In a 10mL Schlenk tube, 0.2mmol of 30, 0.22mmol of zidovudine, 0.1mmol of copper sulfate pentahydrate, 0.2mmol of vitamin C sodium, 2mL of tertiary butanol and 2mL of water are added under the argon atmosphere and stirred at normal temperature for reaction for 20h, wherein the reaction equation is as follows:
(4) In a 10mL Schlemk tube, 0.2mmol, 0.22mmol zidovudine, 0.1mmol copper sulfate pentahydrate, 0.2mmol sodium ascorbate, 2mL tertiary butanol and 2mL water are added under argon atmosphere and stirred at normal temperature for reaction for 20h, wherein the reaction equation is:
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 with ethanol and dichloromethane (EtOH/DCM) to yield both products as white solid products 34, 35 in 83%, 84% yields, respectively.
The foregoing description of the preferred embodiments of the invention is not intended to be limiting, but rather is intended to cover all modifications, equivalents, and alternatives falling within the spirit and principles of the invention.

Claims (4)

1. A process for the preparation of 1,6 dienes, characterized in that it comprises the following steps:
Step (1), adding 0.01-0.25 mmol of palladium catalyst and 0.12-3 mmol of ligand into 2-50 mL of reaction solvent at normal temperature under stirring for 1-6 h to obtain solution 1, adding 0.2-5 mmol of allyl alcohol, 0.4-10 mmol of conjugated diene, 0.4-10 mmol of nucleophile, 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 condition of inert gas atmosphere and 40-120 ℃;
After the reaction is monitored to be complete by TLC, removing the reaction solvent of the reaction liquid, and purifying by a thin layer chromatography/column chromatography to obtain the 1, 6-diene compound;
Wherein, in the step (1):
The palladium catalyst is tetrakis (triphenylphosphine) palladium;
the ligand is 1,1 '-binaphthyl-2, 2' -bisdiphenylphosphine;
The allyl alcohol is any one of cinnamyl alcohol, p-methyl cinnamyl alcohol and 1- (2-methoxyphenyl) prop-2-en-1-ol;
The conjugated diene is any one of 1, 3-butenyl benzene, 4- (p-methyl) -1, 3-butenyl benzene, 1,3, 5-trialkenyl benzene, 1, 3-octadiene and 1, 4-diene;
The nucleophilic reagent is malononitrile;
the calcium catalyst is bis (trifluoromethylsulfonyl) calcium imide;
The additive is any one of potassium hexafluorophosphate, sodium hexafluorophosphate, ammonium hexafluorophosphate, tetraethylammonium tetrafluoroborate and potassium tetrafluoroborate;
The alkali is any one of triethylene diamine, cesium carbonate, triethylamine, potassium tert-butoxide, 1, 5-diazabicyclo [4.3.0] -5-nonene, 1, 8-diazabicyclo [5.4.0] undec-7-ene and 4-dimethylaminopyridine;
The reaction solvent is any one of isopropanol, toluene, N-dimethylacetamide, ethylene glycol dimethyl ether, ethanol, tetrahydrofuran and ethanol.
2. The method of claim 1, wherein in step (1), the ligand is 1,1 '-binaphthyl-2, 2' -bisdiphenylphosphine; the nucleophilic reagent is malononitrile; the additive is potassium hexafluorophosphate; the alkali is triethylene diamine; the solvent is isopropanol.
3. The process according to claim 1, wherein in the step (1), the reaction mixture is obtained by stirring and reacting for 12 to 24 hours under an argon atmosphere at 100 ℃.
4. The process according to claim 1, wherein in step (2), after the completion of the TLC monitoring reaction, the reaction solvent is removed by a vacuum rotary evaporator, the product is separated by thin layer chromatography, and the developing agent is a petroleum ether/ethyl acetate system, wherein the mass ratio of petroleum ether/ethyl acetate=15/1.
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Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
Catalytic stereospecific alkylation of malononitriles with enantioenriched primary allylic amines†;Man-Bo Li等;Chem. Commun.;第49卷;8190-8192 *
Enantioselective Intermolecular Pd-Catalyzed Hydroalkylation of Acyclic 1,3-Dienes with Activated Pronucleophiles;Adamson, Nathan J.等;Journal of the American Chemical Society;第140卷(第8期);2761-2764 *

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