Method for stereoselectively synthesizing cis-disubstituted heteroaryl ethylene and trans-disubstituted heteroaryl ethylene
Through the use of palladium/copper collaborative catalytic system, a three-dimensional selective synthesis of cis and trans-disubstituted heteroaryl ethylene is realized, solving the synthesis difficulties in the prior art, and improving the synthesis efficiency and selectivity.
Patent Information
- Application Number
- CN202410404517.0
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2024-04-07
- Publication Date
- 2025-06-20
AI Technical Summary
The prior art has difficulties in stereoselective synthesis of cis- and trans-disubstituted heteroaryl ethylenes, especially in the absence of prefunctionalized aromatic hydrocarbons as nucleophiles.
Using a palladium/copper collaborative catalytic system, the vinyl C-H heterocyclization reaction of diarylethylene synthesized from ortho-position vinylphenol derivatives and heterocyclic aromatic hydrocarbons is achieved through C-O and double C-H bond activation. This reaction can selectively control the cis and anti-three-dimensional structure of the product.
The substrate limitations based on halogenated aromatic hydrocarbon reaction system were effectively overcome, and the efficient synthesis of cis and trans-disubstituted heteroaryl ethylene was achieved, which improved the stereoselectivity and economicality of the synthesis.
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Abstract
Description
Technical Field
[0001] The present invention belongs to the field of organic synthesis, and particularly relates to a new method for stereoselective synthesis of cis- and trans-disubstituted heteroaryl vinylenes.
Background Art
[0002] Due to their unique chemical and physical properties, polysubstituted ethylenes are widely present in natural products, drugs, and functional material molecules. For example, tetraarylethylene exhibits a strong aggregation-induced emission (AIE) effect and can be used as a material for bioimaging, chemical sensing, and stimuli-responsive applications. Due to the good reactivity flexibility of the C-C double bond, they can also be easily converted into target compounds through addition, hydrogenation, oxidation, and other reactions, and thus play an irreplaceable structural unit in organic synthesis.
[0003] Although polysubstituted ethylenes are very important, their synthesis, especially stereoselective synthesis, is a great challenge for chemists. Traditional methods for constructing double bonds, such as the Wittig reaction, olefin metathesis reaction, and McMurry reaction, can obtain polysubstituted ethylenes, but these methods usually have stereoselectivity problems.
[0004] The palladium migration / vinyl C-H activation strategy well solves the above-mentioned stereoselectivity and regioselectivity problems (iScience, 2020, 23(3): 100966.). Through this strategy, various trisubstituted styrene compounds have been synthesized from ortho-vinyl halide aromatic substrates with high synthesis efficiency. However, so far, no examples of disubstituted styrene products have been reported. These results may be attributed to the coordination of halogen atoms with palladium, which plays a negative role in the process of palladium transfer from aryl to vinyl, especially when the driving force for promoting the shift is small (i.e., the substrate steric hindrance is small). In addition, although aryl borate reagents that need to be pre-synthesized have been used in the synthesis of triarylethylene using this strategy, the situation where un-pre-functionalized aromatic hydrocarbons are used as nucleophiles has not been reported yet.
Summary of the Invention
[0005] In the present invention, we provide an efficient palladium / copper co-catalytic system for the vinyl C-H heterocyclization reaction of diarylethylene formed by C-O and dual C-H bond activation from ortho-vinyl phenol derivatives and heterocyclic aromatic hydrocarbons. The cis- and trans-stereostructures of the products can be selectively controlled by controlling the reaction temperature. This reaction well overcomes the substrate limitation of the previous reaction system based on halide aromatic hydrocarbons. Both cis-diarylethylene and trans-diarylethylene can be stereoselectively produced under the reaction conditions.
[0006] To achieve the above invention purpose, the present invention proposes the following technical solutions:
[0007] A method for the stereoselective synthesis of cis- and trans-disubstituted heteroaryl vinylenes, wherein the structures of the cis- and trans-disubstituted heteroaryl vinylenes are shown in Formula I and Formula II:
[0008]
[0009] Wherein Ar is one of fluorophenyl, chlorophenyl, bromophenyl, methylphenyl, methoxyphenyl, phenyl, naphthyl. The raw materials 2-vinylphenyl trifluoromethanesulfonate, azacyclic compound, as well as a base, a ligand, a catalyst, and an organic solvent are placed in a reaction vessel and mixed, and stirred and reacted at 80-160 °C for 16-48 hours under an inert gas atmosphere; after the reaction is completed, the organic solvent is removed by distillation under reduced pressure and concentrated, and the crude product is separated by column chromatography to obtain the polysubstituted heteroaryl vinyl compound shown in Formula I or Formula II.
[0010] In the synthesis method, the structures of the raw materials 2-vinylphenyl trifluoromethanesulfonate and azacyclic compound are shown in Formula III and Formula IV respectively:
[0011]
[0012] Wherein Ar is one of fluorophenyl, chlorophenyl, bromophenyl, methylphenyl, methoxyphenyl, phenyl, naphthyl.
[0013] In the synthesis method, the inorganic base is selected from at least one of cesium tert-pentanoate, potassium tert-pentanoate, sodium tert-pentanoate, potassium carbonate, cesium carbonate, potassium phosphate.
[0014] In the synthesis method, the organic base is selected from at least one of triethylamine, tri-n-butylamine, triisopropylamine.
[0015] In the synthesis method, the palladium catalyst is selected from at least one of Pd(OAc)2, Pd(PPh3)4, Pd(dba)2, PdCl2, Pd(acac)2, Pd(1.3-dppp)Cl2, Pd(cod)2Cl2, Pd(PPh3)2Cl2.
[0016] In the synthesis method, the copper catalyst is selected from at least one of Cu(OAc)2, CuCl2, Cu(acac)2, CuCl.
[0017] In the synthesis method, the phosphine ligand is selected from at least one of Binap, Tol-Binap, CyJohnphos, Mephos, Davephos, Ruphos, S-phos, X-phos, tBuXphos, dpephos, dppbenz, dppe, dppm, dppp, dppb, dppe, dpph.
[0018] In the synthesis method, the nitrogen ligand is selected from at least one of 1,10-phenanthroline, 2,9-dimethyl-1,10-phenanthroline, 4,7-dimethyl-1,10-phenanthroline, 2,2'-bipyridine, and α,α,α-terpyridine.
[0019] In the synthesis method, the molar ratio of 2-vinylphenyl trifluoromethanesulfonate, azacyclic compound, palladium catalyst, copper catalyst, phosphine ligand, nitrogen ligand, inorganic base, and organic base is 1:1.5:[0.05 - 0.10]:[0.05 - 0.20]:[0.10 - 0.50]:[0.10 - 0.50]:[2.0 - 4.0]:2.0.
[0020] In the synthesis method, the organic solvent is selected from at least one of toluene, p-xylene, anisole, cyclohexane, dioxane, tetrahydrofuran, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, and dimethyl sulfoxide.
[0021] In the synthesis method, the inert gas is selected from at least one of nitrogen, argon, and helium.
[0022] According to the experimental results, the present invention provides a method for synthesizing cis- and trans-disubstituted heteroaryl ethylene compounds by promoting 2-vinylphenyl trifluoromethanesulfonate through an alkali, palladium / copper catalytic system. This method overcomes the problem of stereoselective synthesis of cis- and trans-disubstituted heteroaryl ethylene compounds, improves step economy, and eliminates the separation of intermediate products, thus having great significance for environmental protection.
Description of the Drawings
[0023] Attached Figure 1 and 2 Shown is the synthesis route diagram of the cis- and trans-disubstituted heteroaryl ethylene compounds provided by the present invention. Attached Figure 3 is the nuclear magnetic resonance hydrogen spectrum of (Z)-2-styrylbenz[d]oxazole. Attached Figure 4 is the nuclear magnetic resonance hydrogen spectrum of (Z)-2-(3-methoxystyryl)benz[d]oxazole. Attached Figure 5 is the nuclear magnetic resonance hydrogen spectrum of (E)-2-styrylbenz[d]oxazole. Attached Figure 6 is the nuclear magnetic resonance hydrogen spectrum of (E)-2-(3-(trifluoromethoxy)styryl)benz[d]oxazole.
Specific Embodiments
[0024] The following further illustrates the synthesis method of the present invention in combination with the synthesis examples of the present invention:
[0025] Such asFigure 1 As shown in the figure, the synthesis steps of a cis-disubstituted heteroaryl ethylene compound provided by the present invention are as follows: Take 2-vinylphenyl trifluoromethanesulfonate, a heterocyclic nitrogen compound (molar ratio 100%-150% based on 2-vinylphenyl trifluoromethanesulfonate), an inorganic base (molar ratio 100%-400% based on 2-vinylphenyl trifluoromethanesulfonate), an organic base (molar ratio 200% based on 2-vinylphenyl trifluoromethanesulfonate), a phosphine ligand (molar ratio 5%-15% based on 2-vinylphenyl trifluoromethanesulfonate), a nitrogen ligand (molar ratio 10%-50% based on 2-vinylphenyl trifluoromethanesulfonate), a palladium metal catalyst (molar ratio 1%-10% based on 2-vinylphenyl trifluoromethanesulfonate), a copper metal catalyst (molar ratio 10%-50% based on 2-vinylphenyl trifluoromethanesulfonate), and an organic solvent and place them in a reaction vessel for mixing. Stir and react at 80-120°C for 16-48 hours under a nitrogen environment; after the reaction is completed, concentrate and remove the organic solvent by vacuum distillation, and separate the crude product by column chromatography to obtain the target product.
[0026] As Figure 2 As shown in the figure, the synthesis steps of a cis-disubstituted heteroaryl ethylene compound provided by the present invention are as follows: Take 2-vinylphenyl trifluoromethanesulfonate, a heterocyclic nitrogen compound (molar ratio 100%-150% based on 2-vinylphenyl trifluoromethanesulfonate), an inorganic base (molar ratio 100%-400% based on 2-vinylphenyl trifluoromethanesulfonate), an organic base (molar ratio 200% based on 2-vinylphenyl trifluoromethanesulfonate), a phosphine ligand (molar ratio 5%-15% based on 2-vinylphenyl trifluoromethanesulfonate), a nitrogen ligand (molar ratio 10%-50% based on 2-vinylphenyl trifluoromethanesulfonate), a palladium metal catalyst (molar ratio 1%-10% based on 2-vinylphenyl trifluoromethanesulfonate), a copper metal catalyst (molar ratio 10%-50% based on 2-vinylphenyl trifluoromethanesulfonate), and an organic solvent and place them in a reaction vessel for mixing. Stir and react at 120-160°C for 16-48 hours under a nitrogen environment; after the reaction is completed, concentrate and remove the organic solvent by vacuum distillation, and separate the crude product by column chromatography to obtain the target product.
[0027] The present invention will be further described below in conjunction with specific preparation examples:
[0028] Synthesis Example 1
[0029] (Z)-2-Styrylbenzoxazole Synthesis
[0030] Add 0.20 mmol of 2-vinylphenyl trifluoromethanesulfonate and 0.30 of benzoxazole into the reactor
[0031] mmol, 0.4 mmol of cesium pivalate, 0.4 mmol of triethylamine, 0.01 mmol of Pd(dba)2, Cu(acac)2
[0032] 0.02 mmol, 0.01 mmol of Tol - Binap, 0.02 mmol of 1,10 - Phen, 8.0 mL of dioxane solvent
[0033] React under stirring at 100 °C for 24 hours in a nitrogen atmosphere; after the reaction is completed, concentrate by distillation under reduced pressure to remove the organic solvent, and separate the crude product by column chromatography to obtain the target product with a yield of 75%.
[0034] 1 1H NMR (400 MHz, CDCl3) δ 7.75 - 7.68 (m, 3H), 7.43 - 7.35 (m, 4H), 7.31 (m, 2H), 7.07 (d, J = 12.8 Hz, 1H), 6.57 (d, J = 12.8 Hz, 1H).
[0036] Synthesis Example 2
[0037] Synthesis of (Z)-2-(3 - methoxystyryl)benzoxazole
[0038] Add 0.20 mmol of 4 - methoxy - 2 - vinylphenyl trifluoromethanesulfonate, 0.30 mmol of benzoxazole, 0.4 mmol of cesium pivalate, 0.4 mmol of triethylamine, 0.01 mmol of Pd(dba)2, Cu(acac)2
[0039] 0.02 mmol, 0.01 mmol of Tol - Binap, 0.02 mmol of 1,10 - Phen, 8.0 mL of dioxane solvent. React under stirring at 100 °C for 24 hours in a nitrogen atmosphere; after the reaction is completed, concentrate by distillation under reduced pressure to remove the organic solvent, and separate the crude product by column chromatography to obtain the target product with a yield of 75%.
[0041] 1 1H NMR (400 MHz, CDCl3) δ 7.71 (m, 1H), 7.61–7.57 (m, 1H), 7.43 (m, 1H), 7.36–7.27 (m, 3H), 7.22 (d, J = 7.6 Hz, 1H), 7.04 (d, J = 13.2 Hz, 1H), 6.96–6.91 (m, 1H), 6.56 (d, J = 12.8 Hz, 1H), 3.83 (s, 3H).
[0042] Synthesis Example 3
[0043] Synthesis of (E)-2-Styrylbenz[d]oxazole
[0044] Add 0.20 mmol of 2-Vinylphenyl trifluoromethanesulfonate, 0.30 mmol of benzoxazole, 0.4 mmol of cesium pivalate, 0.4 mmol of triethylamine, 0.01 mmol of Pd(dba)2,
[0045] 0.02 mmol of Cu(acac)2, 0.01 mmol of Tol-Binap, 0.02 mmol of 1,10-Phen, and 8.0 mL of dioxane solvent into the reactor. Stir and react at 160 °C for 36 hours under a nitrogen atmosphere; after the reaction is completed, concentrate and remove the organic solvent by distillation under reduced pressure, and separate the crude product by column chromatography to obtain the target product with a yield of 69%.
[0046] 1 H NMR (400 MHz, CDCl3) δ 7.83 (d, J = 16.4 Hz, 1H), 7.77 - 7.74 (m, 1H), 7.64 (d, J = 7.2 Hz, 2H), 7.59 - 7.54 (m, 1H), 7.49 - 7.35 (m, 5H), 7.12 (d, J = 16.4 Hz, 1H).
[0048] Synthesis Example 4
[0049] (E)-2-(3-(Trifluoromethoxy)styryl)benz[d]oxazole
[0050] Add 0.20 mmol of 4-Trifluoromethoxy-2-vinylphenyl trifluoromethanesulfonate, 0.30 mmol of benzoxazole, 0.4 mmol of cesium pivalate, 0.4 mmol of triethylamine, 0.01 mmol of Pd(dba)2, 0.02 mmol of Cu(acac)2, 0.01 mmol of Tol-Binap, 0.02 mmol of 1,10-Phen, and 8.0 mL of dioxane solvent into the reactor. Stir and react at 160 °C for 36 hours under a nitrogen atmosphere; after the reaction is completed, concentrate and remove the organic solvent by distillation under reduced pressure, and separate the crude product by column chromatography to obtain the target product with a yield of 69%.
[0051] 1 H NMR (400 MHz, CDCl3) δ 7.78 - 7.71 (m, 2H), 7.56 - 7.50 (m, 2H), 7.47 - 7.41 (m, 2H), 7.39 - 7.31 (m, 2H), 7.26 - 7.21 (m, 1H), 7.10 (d, J = 16.4 Hz, 1H).
[0053] It should be noted that the above embodiments do not constitute a limitation on the scope of protection required by the present invention. For those of ordinary skill in the art, without departing from the concept of the present invention, several modifications and improvements can still be made, and these all fall within the scope of protection of the present invention.
Claims
1. A method for stereoselectively synthesizing cis- and trans-disubstituted heteroarylethenes, comprising the following steps: The raw materials 2-vinylphenyl trifluoromethanesulfonate, nitrogen heterocyclic compound, base, ligand, catalyst and organic solvent are placed in a reaction container and mixed, and stirred at 80-160° C. for 16-48 hours under an inert gas environment; after the reaction, the organic solvent is removed by vacuum distillation and concentration, and the crude product is separated by column chromatography to obtain a polysubstituted aromatic methyl compound as shown in Formula I. Ar in Formula I is one of fluorophenyl, chlorophenyl, bromophenyl, methylphenyl, methoxyphenyl, phenyl and naphthyl. Ar in formula II is one of fluorophenyl, chlorophenyl, bromophenyl, methylphenyl, methoxyphenyl, phenyl and naphthyl.
2. The method for stereoselective synthesis of cis- and trans-disubstituted heteroarylethenes according to claim 1, characterized in that The structures of the raw materials 2-vinylphenyl trifluoromethanesulfonate and the nitrogen heterocyclic compound are respectively shown in Formula III and Formula IV Ar in formula IV is one of fluorophenyl, chlorophenyl, bromophenyl, methylphenyl, methoxyphenyl, phenyl and naphthyl.
3. The method for stereoselective synthesis of cis- and trans-disubstituted heteroarylethenes according to claim 1, characterized in that: The inorganic base is selected from at least one of cesium tert-valerate, potassium tert-valerate, sodium tert-valerate, potassium carbonate, cesium carbonate and potassium phosphate.
4. The method for stereoselective synthesis of cis- and trans-disubstituted heteroarylethenes according to claim 1, characterized in that: The organic base is selected from at least one of triethylamine, tri-n-butylamine and triisopropylamine.
5. The method for stereoselective synthesis of cis- and trans-disubstituted heteroarylethenes according to claim 1, characterized in that: The palladium catalyst is selected from at least one of Pd(OAc)2, Pd(PPh3)4, Pd(dba)2, PdCl2, Pd(acac)2, Pd(1.3-dppp)Cl2, Pd(cod)2Cl2, and Pd(PPh3)2Cl2.
6. The method for stereoselective synthesis of cis- and trans-disubstituted heteroarylethenes according to claim 1, characterized in that: The copper catalyst is selected from at least one of Cu(OAc)2, CuCl2, Cu(acac)2, and CuCl.
7. The method for stereoselective synthesis of cis- and trans-disubstituted heteroarylethenes according to claim 1, characterized in that: The phosphine ligand is selected from at least one of Binap, Tol-Binap, CyJohnphos, Mephos, Davephos, Ruphos, S-phos, X-phos, tBuXphos, dpephos, dppbenz, dppe, dppm, dppp, dppb, dppe, and dpph.
8. The method for stereoselective synthesis of cis- and trans-disubstituted heteroarylethenes according to claim 1, characterized in that: The nitrogen ligand is selected from at least one of 1,10-phenanthroline, 2,9-dimethyl-1,10-phenanthroline, 4,7-dimethyl-1,10-phenanthroline, 2,2'-bipyridine, and α,α,α-terpyridine.
9. The method for stereoselective synthesis of cis- and trans-disubstituted heteroarylethenes according to claim 1, characterized in that: In the synthesis method, the molar ratio of 2-vinylphenyl trifluoromethanesulfonate, nitrogen heterocyclic compound, palladium catalyst, copper catalyst, phosphine ligand, nitrogen ligand, inorganic base and organic base is 1:1.5:[0.05-0.10]:[0.05-0.20]:[0.10-0.50]:[0.10-0.50]:[2.0-4.0]:2.
0.
10. The method for stereoselective synthesis of cis- and trans-disubstituted heteroarylethenes according to claim 1, characterized in that: The organic solvent is selected from at least one of toluene, p-xylene, anisole, cyclohexane, dioxane, tetrahydrofuran, acetonitrile, N,N-dimethylformamide and dimethyl sulfoxide.
11. The method for stereoselective synthesis of cis- and trans-disubstituted heteroarylethenes according to claim 1, characterized in that: The inert gas is selected from at least one of nitrogen, argon and helium.