CN113683493B - A kind of electron-rich conjugated diene compound, preparation method and application - Google Patents

Abstract

The invention discloses an electron-rich conjugated diene compound, a preparation method and application thereof, wherein the electron-rich conjugated diene compound comprises the following steps: step 1: mixing N- (3- (benzyloxy) cyclobutyl) -4-methylbenzenesulfonylhydrazone, a base and a catalyst; step 2: adding a phosphine ligand, aryl halide and a solvent, and fully reacting under magnetic stirring at 90 ℃ in a nitrogen atmosphere; and step 3: cooling and purifying to obtain the required electron-rich conjugated diene compound; or preparing the electron-rich conjugated diene compound by a one-step method; the preparation method of the electron-rich 1, 3-butadiene has good substrate universality and good functional group compatibility; the aromatic ring can be substituted by groups such as electron-deficient groups, electron-rich groups, heterocyclic rings, naphthalene rings and the like, the reaction condition is mild, and the obtained product has a single structure and is E-type electron-rich 1,3 butadiene; and the product 1,3 conjugated diene can be combined with alkene and alkyne to obtain the product of [4+2] cyclization in better yield.

Description

A kind of electron-rich conjugated diene compound, preparation method and application

technical field

The invention relates to the technical field of conjugated dienes, in particular to an electron-rich conjugated diene compound, a preparation method and an application.

Background technique

As an important skeleton in organic synthesis, 1,3-butadiene compounds have conjugated systems and are widely used in cycloaddition and polymerization reactions. Among them, electron-rich conjugated dienes are commonly used substrates for [4+2] cyclization, and Diels-Alder reactions with dienophiles (alkenes or alkynes) can be used to construct six-membered rings , is one of the most important means of forming carbon-carbon bonds in organic chemical synthesis reactions. It is also an important intermediate for the synthesis of biologically active compounds. For example, the [4+2] cyclization of naphthoquinones can provide a feasible method for the synthesis of anthraquinone antibiotics. In addition, such electron-rich conjugated dienes have also been reported in the fields of polymerization.

At present, one way to synthesize such electron-rich conjugated dienes is through the intermolecular metathesis reaction of enol ether-alkynes catalyzed by ruthenium. This method mainly uses the enol ether of the alkyl group as the substrate, and there is a problem of stereoselectivity. Or through the ylide reaction, a substrate is first prepared into a phosphorus ylide, and then reacted with the corresponding enone. The disadvantage of this method is that after the phosphine is generated in the reaction process, the post-processing is more complicated. If a single E Isomers, the reaction needs to be carried out at a lower temperature, the reaction time is long, and there are many shortcomings in the reaction steps.

SUMMARY OF THE INVENTION

Aiming at the problems in the prior art, the present invention provides an electron-rich conjugated diene compound with better stereoselectivity, simple operation and convenience, a preparation method and an application.

The technical scheme adopted in the present invention is: a kind of electron-rich conjugated diene compound, and its structure is as follows:

In the formula: Ar is phenyl, 4-methylphenyl, 4-tert-butylphenyl, 4-methoxyphenyl, 4-phenyl, 4-fluorophenyl, 4-chlorobenzene, 4-tris Fluoromethylphenyl, 3-methoxyphenyl, 2-methylphenyl, 2-methoxyphenyl, 1,2-methylenedioxyphenyl, 2-naphthyl, 3-thienyl one of the.

The preparation method of electron-rich conjugated diene compound comprises the following steps:

Step 1: Mix N-(3-(benzyloxy)cyclobutyl)-4-methylbenzenesulfonylhydrazone, base and catalyst;

Step 2: Add phosphine ligand, aryl halide and solvent, and fully react under magnetic stirring, 90°C temperature and nitrogen atmosphere;

Step 3: After cooling, the desired electron-rich conjugated diene compound can be obtained by purification.

The preparation method of electron-rich conjugated diene compound comprises the following steps:

Step 1: Mix 3-(benzyloxy)cyclobutan-1-one, p-toluenesulfonyl hydrazide and solvent, and fully react under magnetic stirring and 60°C temperature;

Step 2: After cooling, add alkali, metal palladium, phosphine ligand, aryl halide and solvent to the reaction mixture obtained in step 1; fully react under magnetic stirring conditions, 90°C temperature, and nitrogen atmosphere;

Step 3: After cooling, the desired electron-rich conjugated diene compound can be obtained by purification.

Further, the base is cesium carbonate, the catalyst is metal palladium, the phosphine ligand is diphenylcyclohexylphosphine, and the solvent is 1,4 dioxane.

Further, the catalyst is one of palladium acetate, tris(dibenzylideneacetone)dipalladium, bis(acetonitrile)dichloropalladium(II), and allylpalladium(II) chloride dimer.

Further, the molar ratio of the aryl halide to N-(3-(benzyloxy)cyclobutyl)-4-methylbenzenesulfonylhydrazone or p-toluenesulfonylhydrazide is both 1:1-1.5.

Further, the molar ratio of the catalyst and the phosphine ligand is 1:2-4, the molar ratio of the aromatic halide and the catalyst is 1:0.04, and the molar ratio of the aromatic halide and the base is 1:2.5-3.

Further, the molar ratio of the 3-(benzyloxy)cyclobutan-1-one to the aryl halide is 6:5.

An application of an electron-rich conjugated diene compound. The electron-rich conjugated diene compound is used as a substrate for [4+2] cyclization to react with a dienophile to construct a six-membered ring compound.

The beneficial effects of the present invention are:

(1) The preparation method of the present invention has Z/E selectivity, and the obtained electron-rich conjugated diene is E-type 1,3-butadiene with a single structure;

(2) the present invention synthesizes electron-rich conjugated diene by one step of simple and easy-to-obtain bromobenzene, cyclobutanone-derived p-toluenesulfonyl hydrazone, the preparation method is simple, and the operation is convenient;

(3) The electron-rich conjugated diene obtained by the present invention is a common substrate for [4+2] cyclization, and can construct six-membered ring compounds with a yield of more than 85%.

Description of drawings

Figure 1 is a schematic diagram of the preparation process of Examples 1-3.

FIG. 2 is a schematic diagram of the preparation process of Example 4. FIG.

FIG. 3 is a schematic diagram of the preparation process of Example 5. FIG.

FIG. 4 is the hydrogen nuclear magnetic resonance spectrum of the product of Example 1. FIG.

Figure 5 is the carbon nuclear magnetic resonance spectrum of the product of Example 1.

Figure 6 is a high-resolution mass spectrum of the product of Example 1.

FIG. 7 is the hydrogen nuclear magnetic resonance spectrum of the product of Example 5. FIG.

Figure 8 is the carbon nuclear magnetic resonance spectrum of the product of Example 5.

FIG. 9 is a high-resolution mass spectrum of the product of Example 5. FIG.

Detailed ways

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

An electron-rich conjugated diene compound, the structure of which is as follows:

In the formula: Ar is phenyl, 4-methylphenyl, 4-tert-butylphenyl, 4-methoxyphenyl, 4-phenyl, 4-fluorophenyl, 4-chlorobenzene, 4-tris Fluoromethylphenyl, 3-methoxyphenyl, 2-methylphenyl, 2-methoxyphenyl, 1,2-methylenedioxyphenyl, 2-naphthyl, 3-thienyl one of the.

The preparation method of the electron-rich conjugated diene compound is shown in Figure 1, including the following steps:

Step 1: Mix N-(3-(benzyloxy)cyclobutyl)-4-methylbenzenesulfonylhydrazone, base and catalyst;

Step 2: Add phosphine ligand, aryl halide and solvent, and fully react under magnetic stirring, 90°C temperature and nitrogen atmosphere;

Step 3: After cooling, the desired electron-rich conjugated diene compound can be obtained by purification.

The preparation method of the electron-rich conjugated diene compound is shown in Figure 2, and includes the following steps:

Step 1: Mix 3-(benzyloxy)cyclobutan-1-one, p-toluenesulfonyl hydrazide and solvent, and fully react under magnetic stirring and 60°C temperature;

Step 2: After cooling, add alkali, metal palladium, phosphine ligand, aryl halide and solvent to the reaction mixture obtained in step 1; fully react under magnetic stirring conditions, 90°C temperature, and nitrogen atmosphere;

Step 3: After cooling, the desired electron-rich conjugated diene compound can be obtained by purification. Purification was carried out using a silica gel column.

The base is cesium carbonate, the catalyst is metal palladium, the phosphine ligand is diphenylcyclohexylphosphine, and the solvent is 1,4 dioxane. The catalyst is one of palladium acetate, tris(dibenzylideneacetone)dipalladium, bis(acetonitrile)dichloride palladium(II) and allylpalladium(II) chloride dimer. The molar ratio of the aryl halide to N-(3-(benzyloxy)cyclobutyl)-4-methylbenzenesulfonylhydrazone or p-toluenesulfonylhydrazide is 1:1-1.5. The molar ratio of catalyst and phosphine ligand is 1:2-4, the molar ratio of aromatic halide and catalyst is 1:0.04, and the molar ratio of aromatic halide and base is 1:2.5-3. 3-(benzyloxy)cyclobutane The molar ratio of alk-1-one to aryl halide was 6:5.

Electron-rich conjugated dienes act as substrates for [4+2] cyclization and react with dienophiles to construct six-membered rings.

An aromatic halide is an aryl bromide that is any of the following structures:

Electron-rich conjugated diene compounds, which are any of the following structures:

Example 1

The electron-rich 1,3-butadiene was prepared as follows:

Step 1: To an 8 mL vial equipped with a magnetic stir bar was added 0.5 mmol of cesium carbonate, 0.24 mmol of N-(3-(benzyloxy)cyclobutyl)-4-methylbenzenesulfonylhydrazone, 0.004 mmol of tris(di(di)) benzylideneacetone) dipalladium, the vial was sealed with a screw cap and transferred to the glove box.

Step 2: Add 0.008 mmol diphenylcyclohexylphosphine, 2.0 mL 1,4-dioxane and 0.2 mmol bromobenzene to the vial, cap screw and transfer out of glove box. Stir on a magnetic stirrer at 90°C for 16 hours.

Step 3: Cool to room temperature, filter the obtained reaction solution with celite, elute with ethyl acetate, spin dry under vacuum, transfer to silica gel chromatography column, use eluent (PE/EA=100:1 ) eluted to obtain the target compound as a colorless oil (Rf=0.5 (PE·EA=40:1)) in a yield of 79%.

Its structure is:

The reaction process is as follows:

The H NMR spectrum of the product is shown in Figure 4:

¹ H NMR (400MHz, CDCl3) δ7.45-7.23 (m, 10H), 6.55 (d, J=12.6Hz, 1H), 5.90 (d, J=12.6Hz, 1H), 5.09 (d, J=1.7 Hz, 1H), 4.91 (d, J=1.8 Hz, 1H), 4.80 (s, 2H).

The carbon NMR spectrum of the product is shown in Figure 5:

¹³ C NMR (101 MHz, CDCl ₃ ) 150.4, 145.4, 140.8, 136.7, 128.5, 128.1, 128.0, 128.0, 127.5, 127.4, 111.9, 108.8, 71.9.

The high-resolution mass spectrum of the product is shown in Figure 6:

Its high-resolution mass spectrum is: HRMS (ESI, m/z): calcd for C ₁₇ H ₁₇ O[M+H] ⁺ 237.1274, found237.1274.

Example 2

The electron-rich 1,3-butadiene was prepared as follows:

Step 1: To an 8 mL vial equipped with a magnetic stir bar was added 0.5 mmol of cesium carbonate, 0.24 mmol of N-(3-(benzyloxy)cyclobutyl)-4-methylbenzenesulfonylhydrazone, 0.004 mmol of tris(di(di)) benzylideneacetone) dipalladium, the vial was sealed with a screw cap and transferred to the glove box.

Step 2: Add 0.008 mmol diphenylcyclohexylphosphine, 2.0 mL 1,4-dioxane and 0.2 mmol aryl bromide (Ar is naphthyl) to vial, cap screw and transfer out of glove box . Stir on a magnetic stirrer at 90°C for 16 hours.

Step 3: Cool to room temperature, filter the obtained reaction solution with celite, elute with ethyl acetate, spin dry under vacuum, transfer to silica gel chromatography column, use eluent (PE/EA=100:1 ) eluted to give the target compound as a colorless oil (Rf=0.5 (PE·EA=40:1)) in a yield of 60%.

The reaction process is as follows:

The H NMR spectrum of the product is: ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.83-7.76 (m, 4H), 7.50-7.44 (m, 3H), 7.39-7.28 (m, 5H), 6.58 (d, J=12.7Hz, 1H), 5.98 (d, J=12.7Hz, 1H), 5.18 (s, 1H), 5.04 (s, 1H), 4.81 (s, 2H).

The carbon nuclear magnetic resonance spectrum of the product is: ¹³ C NMR (101 MHz, CDCl ₃ ) δ 150.7, 145.4, 138.3, 136.8, 133.4, 132.9, 128.6, 128.1, 128.1, 127.6, 127.6, 126.7, 126.5, 126.1, 125.9, 112.5, 108 ,72.0.

The high resolution mass spectrum of the product is: HRMS (ESI, m/z): C ₂₁ H ₁₉ O [M+H] ⁺ 287.1430, calcd for 287.1429.

Example 3

The electron-rich 1,3-butadiene was prepared as follows:

Step 1: To an 8 mL vial equipped with a magnetic stir bar was added 0.5 mmol of cesium carbonate, 0.24 mmol of N-(3-(benzyloxy)cyclobutyl)-4-methylbenzenesulfonylhydrazone, 0.004 mmol of tris(di(di)) benzylideneacetone) dipalladium, the vial was sealed with a screw cap and transferred to the glove box.

Step 2: Add 0.008 mmol of diphenylcyclohexylphosphine, 2.0 mL of 1,4-dioxane and 0.2 mmol of aryl bromide (Ar is thiophene) to the vial, cap screw and transfer out of glove box. Stir on a magnetic stirrer at 90°C for 16 hours.

Step 3: Cool to room temperature, filter the obtained reaction solution with celite, elute with ethyl acetate, spin dry under vacuum, transfer to silica gel chromatography column, use eluent (PE/EA=100:1 ) eluted to obtain the target compound as a colorless oil (Rf=0.5 (PE·EA=40:1)) in a yield of 73%.

The H NMR spectrum of the product is: ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.87-7.74 (m, 2H), 7.38-7.23 (m, 8H), 6.39 (d, J=12.6Hz, 1H), 5.99 (d, J=12.7 Hz, 1H), 5.27 (d, J=2.0 Hz, 1H), 5.00 (d, J=2.1 Hz, 1H), 4.73 (s, 2H).

The reaction process is as follows:

The CNMR spectrum of the product is:

¹³ C NMR (101 MHz, CDCl ₃ ) δ 150.8, 140.0, 139.5, 138.4, 136.6, 136.4, 128.5, 128.0, 127.4, 124.2, 124.0, 123.8, 123.5, 122.6, 114.1, 109.0, 72.0.

High resolution mass spectrum is: HRMS (ESI, m/z): calcd for C ₁₉ H ₁₇ OS [M+H] ⁺ 293.0995, found 293.0995.

Example 4

The electron-rich 1,3-butadiene was prepared as follows:

Step 1: To an 8 mL vial equipped with a magnetic stir bar was added 0.24 mmol 3-(benzyloxy)cyclobutan-1-one, 0.24 mmol p-toluenesulfonylhydrazide, 1.0 mL 1,4-dioxane. The resulting solution was sealed and stirred on a magnetic stirrer at 60°C for 1 hour.

Step 2: After the reaction solution was cooled to room temperature, 0.5mmol of cesium carbonate, 0.004mmol of tris(dibenzylideneacetone)dipalladium, 0.008mmol of diphenylcyclohexylphosphine, 1.0mL of 1,4-dipalladium were added to the reaction mixture oxane and 0.2 mmol of bromobenzene. Cap the screw cap and transfer out of the glove box and place on a magnetic stirrer at 90°C for 16 hours.

Step 3: Cool to room temperature, filter the obtained reaction solution with celite, elute with ethyl acetate, spin dry under vacuum, transfer to a silica gel chromatography column, and elute with (PE/EA=100:1) eluted with solvent to obtain the target compound as a colorless oil (Rf=0.5 (PE·EA=40:1)) in a yield of 67%.

The reaction process is as follows:

Exploring the [4+2] cyclization of some compounds, in which electron-rich conjugated dienes are commonly used substrates for [4+2] cyclization, which interacts with dienophiles (alkenes or alkynes) The Ers-Alder reaction can be used to construct six-membered ring compounds, and it is one of the most important ways to form carbon-carbon bonds in organic chemical synthesis reactions. Example 5 is taken as an example for description.

Example 5

Follow these steps:

A 4 mL vial equipped with a magnetic stir bar was charged with 0.2 mmol of 1-phenyl-1H-pyrrole-2,5-dione and 0.6 mL of toluene was added. Then, 0.2 mmol of conjugated diene was added. The resulting reaction mixture was stirred at 80°C under nitrogen atmosphere for 15 hours. After cooling to room temperature, the reaction mixture was concentrated in vacuo. The crude mixture was purified by column chromatography on silica gel (PE:EA=5:1) to provide the product as a white solid in 88% yield. The product structure is as follows:

The reaction process is as follows:

The H NMR spectrum of the product is shown in Figure 7: ¹ H NMR (400MHz, CDCl ₃ )δ7.48-7.25(m, 12H), 7.24(s, 1H), 7.20-7.12(m, 2H), 6.45( dd,J＝5.5,2.3Hz,1H),4.77-4.70(m,1H),4.58(d,J＝11.4Hz,1H),4.50(d,J＝11.4Hz,1H),3.37(td,J = 9.4, 7.1 Hz, 1H), 3.25 (dd, J=9.8, 4.5 Hz, 1H), 3.19-3.04 (m, 2H).

The carbon nuclear magnetic resonance spectrum of the product is shown in Figure 8: ¹³ C NMR (101 MHz, CDCl ₃ ) δ 179.0, 175.8, 143.2, 139.7, 137.8, 132.1, 129.0, 128.5, 128.4, 128.3, 128.2, 127.6, 127.5, 126.7, 125.6 , 123.2, 123.1, 70.7, 70.6, 45.0, 37.6, 25.4.

The high resolution mass spectrum of the product is shown in Figure 9: HRMS (ESI, m/z): calcd for C ₂₇ H ₂₃ NNaO ₃ [M+Na] ⁺ 432.1570, found 432.1574.

Compared with the existing method, the preparation method of the electron-rich conjugated diene compound of the present invention is mainly obtained by ring-opening isomerization of a four-membered ring, and has good stereospecificity and can be selectively The product of type E is obtained. The 1,3-butadiene obtained by this method is obtained by thermal ring-opening isomerization of the four-membered ring, and the thermal ring-opening of the four-membered ring can be obtained by inward and outward rotation to obtain Z-type or E-type or a mixed product of the two . One of the influencing factors of thermal ring-opening of four-membered rings is the substituent at the 3-position of cyclobutene. As the electron-donating properties of the substituent group increase, the preference of the substituent group in the ring-opening isomerization product increases. .

The raw material used in the present invention is beneficial to produce the product of E-type structure.

The method has the advantages of simple preparation of raw materials, mild reaction conditions, few reaction steps and simple reaction operation. The preparation method of electron-rich 1,3 butadiene in the present invention has the advantages of good substrate universality, good functional group compatibility, and can replace electron-deficient, electron-rich, heterocyclic, naphthalene ring and other groups on aromatic rings, and the reaction conditions Mild, the obtained products have a single structure and are all E-type 1,3 butadienes.

Claims (5)

1. a preparation method of electron-rich conjugated diene compound, is characterized in that, comprises the following steps: Step 1: Mix N-(3-(benzyloxy)cyclobutyl)-4-methylbenzenesulfonylhydrazone, a base and a catalyst; the base is cesium carbonate, and the catalyst is tris(dibenzylideneacetone)dipalladium ; Step 2: add phosphine ligand, aryl halide and solvent, and fully react under magnetic stirring, 90°C temperature, and nitrogen atmosphere; the phosphine ligand is diphenylcyclohexylphosphine, and the solvent is 1,4 dioxane; Step 3: after cooling, the desired electron-rich conjugated diene compound is obtained by purification; Electron-rich conjugated diene compounds with the following structure:

In the formula: Ar is phenyl, 4-methylphenyl, 4-tert-butylphenyl, 4-methoxyphenyl, 4-fluorophenyl, 4-chlorobenzene, 4-trifluoromethylphenyl , one of 3-methoxyphenyl, 2-methylphenyl, 2-methoxyphenyl, 1,2-methylenedioxyphenyl, 2-naphthyl, and 3-thienyl. 2. a preparation method of electron-rich conjugated diene compound, is characterized in that, comprises the following steps: Step 1: Mix 3-(benzyloxy)cyclobutan-1-one, p-toluenesulfonyl hydrazide and solvent, and fully react under magnetic stirring and 60°C temperature; Step 2: After cooling, add base, catalyst metal palladium, phosphine ligand, aryl halide and solvent to the reaction mixture obtained in step 1; fully react under magnetic stirring conditions, 90°C temperature, and nitrogen atmosphere; the base is carbonic acid Cesium, the catalyst metal palladium is tris(dibenzylideneacetone)dipalladium; the phosphine ligand is diphenylcyclohexylphosphine, and the solvent is 1,4 dioxane; Step 3: after cooling, the desired electron-rich conjugated diene compound is obtained by purification; Electron-rich conjugated diene compounds with the following structure:

In the formula: Ar is phenyl, 4-methylphenyl, 4-tert-butylphenyl, 4-methoxyphenyl, 4-fluorophenyl, 4-chlorobenzene, 4-trifluoromethylphenyl , one of 3-methoxyphenyl, 2-methylphenyl, 2-methoxyphenyl, 1,2-methylenedioxyphenyl, 2-naphthyl, and 3-thienyl. 3. the preparation method of a kind of electron-rich conjugated diene compound according to claim 1 and 2, is characterized in that, described aryl halide and N-(3-(benzyloxy) cyclobutyl)- The molar ratio of 4-methylbenzenesulfonylhydrazone or p-toluenesulfonylhydrazide is 1:1-1.5. 4. the preparation method of a kind of electron-rich conjugated diene compound according to claim 1 or 2, is characterized in that, the molar ratio of described catalyst and phosphine ligand is 1:2～4, aromatic halide and catalyst The molar ratio is 1:0.04, and the molar ratio of aromatic halide and base is 1:2.5-3. 5. the preparation method of a kind of electron-rich conjugated diene compound according to claim 2, is characterized in that, the mol ratio of described 3-(benzyloxy) cyclobutan-1-one and aryl halide 6:5.

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