A method for the preparation of cis-olefins regulated by quaternary ammonium salts
The use of a palladium catalyst system regulated by quaternary ammonium salts to catalyze the preparation of cis-olefins from diarylacetylene at ambient temperature and pressure solves the problems of poor stereoselectivity and environmental pollution in existing technologies, and realizes efficient and low-cost cis-olefin synthesis.
Patent Information
- Application Number
- CN202610890925.0
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2026-06-18
- Publication Date
- 2026-11-03
AI Technical Summary
Existing technologies for synthesizing cis-olefins suffer from problems such as poor stereoselectivity, harsh reaction conditions, and the environmentally unfriendly use of heavy metal catalysts, making it difficult to meet the demand for high-purity cis-stilbene.
Quaternary ammonium salts were used as additives to regulate the palladium catalyst. By introducing hydrogen gas under anhydrous and oxygen-free conditions, the palladium salt catalyst was used to catalyze the preparation of cis-olefins from diarylaceyne at room temperature and pressure. The reaction process was monitored by combining thin-layer chromatography and gas chromatography-mass spectrometry, and finally purification and separation were performed.
This method enables highly selective synthesis of cis-olefins under mild conditions, avoiding the need for high-temperature and high-pressure equipment, reducing energy consumption and production costs, and preventing heavy metal pollution, thus meeting the requirements of environmentally friendly chemistry.
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Figure CN123026490A_ABST
Abstract
Description
Technical Field
[0001] This invention relates to the field of organic synthesis technology, specifically to a method for preparing cis-olefins regulated by quaternary ammonium salts. Background Technology
[0002] Alkenes are widely found in pharmaceuticals, natural products, and fragrances, and their molecular structure has significant biological importance. The stereochemical structure of the carbon-carbon double bonds in alkene molecules directly determines their biological activities (such as the therapeutic effects of drugs and the physiological functions of natural products). Therefore, developing methods for stereoselectively constructing alkenes, especially synthetic techniques that precisely control the configuration of double bonds, has become a key requirement in the field of organic synthesis.
[0003] It is well known that trans-olefins are thermodynamically more stable than cis-olefins, making their synthesis more challenging. However, for many natural products or drug molecules, the cis configuration often exhibits superior biological activity and is more beneficial to humans. For example, the cis-stilbene derivative Combrestatin A-4 is an effective microtubule inhibitor exhibiting excellent antitumor activity, while its trans isomer lacks this activity; and resveratrol, in its cis configuration, promotes DNA repair, while its trans configuration has an inhibitory effect. Currently, the synthesis of cis-diarylethylene mainly relies on methods such as Witting reaction, Perkin condensation, Heck coupling, and alkyne selective reduction. Among these, the route of selective reduction of cis-stilbene from diphenylacetylene via carbon-carbon triple bonds has attracted attention due to the readily available raw materials and simple reaction steps. For example, the catalytic reduction of diarylacetylene using a Lindra palladium catalyst is a classic method. However, these traditional stilbene synthesis techniques still have certain limitations. Lindlapalladium catalysts have been widely recognized for their catalytic efficiency and effectiveness, but the heavy metals they contain do not conform to the principles of green chemistry and may pose a threat to human health and the environment. The Witting reaction constructs a C-C double bond through the condensation of benzaldehyde and benzyltriphenylphosphine, but the main product of this reaction is trans-stilbene, while the yield of cis-stilbene is extremely low (generally less than 20%), and the products are not singular, usually being a mixture of cis and trans isomers. Therefore, subsequent separation and purification are difficult and costly, making it difficult to meet the application requirements of high-purity cis products. Although the Perkin condensation reaction can synthesize substituted stilbene derivatives, the reaction requires a high-temperature and strong-alkali environment, has poor functional group tolerance, and also suffers from poor stereoselectivity, which is not conducive to the synthesis of complex cis-stilbene derivatives.
[0004] Therefore, developing a method for converting diphenylacetylene to cis-stilbene with high stereoselectivity, mild reaction conditions, and environmental friendliness has significant application prospects. It can effectively address the pain points of existing technologies and meet the demand for high-purity cis-stilbene in fields such as medicine and materials. Summary of the Invention
[0005] To address or partially address the problems existing in related technologies, the present invention aims to provide a method for preparing cis-olefins regulated by quaternary ammonium salts, specifically comprising the following steps: (1) Under anhydrous and oxygen-free conditions, palladium salt catalyst, quaternary ammonium salt additive, solvent and diarylacetylene are added to the reaction vessel to obtain the reaction system; hydrogen atmosphere is introduced into the reaction system and then the reaction is stirred.
[0006] (2) The reaction process was monitored by thin-layer chromatography (TLC) and gas chromatography-mass spectrometry (GC-MS). After the reaction was completed, the product was purified and separated to obtain the cis-olefin product.
[0007] Preferably, the structural formula of the diarylacetylene in step (1) of the present invention is as follows: , where R 1 For -H, -Me, -OMe, - i- Pr、- t One of -Bu, -F, -Cl, -Br, -COOMe, -CN, R 2 For -H, -Me, -OMe, - i- Pr、- t One of -Bu, -F, -Cl, -Br, -COOMe, -CN, R 1 and R 2 They can be the same or different.
[0008] Preferably, the palladium salt catalyst in step (1) of the present invention is any one of palladium acetate, tetra(triphenylphosphine)palladium, tris(dibenzylacetone)palladium, palladium bromide, palladium iodide, palladium chloride, palladium trifluoroacetate, palladium on carbon, and palladium tetrafluoroborate tetraacetonitrile.
[0009] Preferably, the quaternary ammonium salt additive in step (1) of the present invention is any one of tetrabutylammonium iodide, tetrabutylammonium bromide, tetrabutylammonium chloride, tetrabutylammonium hexafluorophosphate, tetrabutylammonium perchlorate, tetrabutylammonium acetate, and tetrabutylammonium fluoride.
[0010] Preferably, the solvent in step (1) of the present invention is one or more of methanol, toluene, ethanol, isopropanol, tetrahydrofuran, acetonitrile, dioxane, dichloroethane and N,N-dimethylformamide; more preferably, the solvent is a mixed solvent of toluene and methanol in a volume ratio of 3:1.
[0011] Preferably, in step (1) of the present invention, the molar ratio of palladium salt catalyst, quaternary ammonium salt additive and diarylacetylene is 0.0001~0.001:0.01~0.3:1; more preferably, the molar ratio of palladium salt catalyst, quaternary ammonium salt additive and diarylacetylene is 0.0001:0.01:1.
[0012] Preferably, the concentration of diarylacetylene in the reaction system in step (1) of the present invention is 0.05~1 mol / L.
[0013] Preferably, the pressure after introducing hydrogen atmosphere in step (1) of the present invention is 0.6-1.4 atm.
[0014] Preferably, the temperature of the stirring reaction in step (1) of the present invention is 15-35°C. o C.
[0015] This invention provides a method for preparing cis-olefins regulated by quaternary ammonium salts, which has the following beneficial effects: (1) The reaction conditions of this invention are milder, and the reaction can occur at room temperature and normal pressure. It does not require high temperature and high pressure equipment, has lower energy consumption, and is safer. It can greatly reduce production costs and has the potential for industrial application. It is expected to generate significant social and economic benefits.
[0016] (2) The present invention uses quaternary ammonium salt as a key additive to regulate the catalytic activity of palladium catalyst and exhibits good chemoselectivity and stereoselectivity.
[0017] (3) The catalytic system constructed in this invention avoids the use of highly toxic heavy metal reagents compared with the Lindela palladium catalyst, and is more in line with the characteristics of environmentally friendly chemistry. Attached Figure Description
[0018] Figure 1 It is compound 2a obtained in Example 1 of this invention. 1 H NMR spectrum.
[0019] Figure 2 It is compound 2a obtained in Example 1 of this invention. 13 C10 NMR spectrum.
[0020] Figure 3 It is compound 2b obtained in Example 2 of this invention. 1 H NMR spectrum.
[0021] Figure 4 It is compound 2b obtained in Example 2 of this invention. 13 C10 NMR spectrum.
[0022] Figure 5 It is compound 2c obtained in Example 3 of this invention. 1 H NMR spectrum.
[0023] Figure 6 It is compound 2c obtained in Example 3 of this invention. 13 C10 NMR spectrum.
[0024] Figure 7 It is compound 2d obtained in Example 4 of this invention. 1 H NMR spectrum.
[0025] Figure 8 It is compound 2d obtained in Example 4 of this invention. 13 C10 NMR spectrum.
[0026] Figure 9 It is compound 2e obtained in Example 5 of this invention. 1 H NMR spectrum.
[0027] Figure 10 It is compound 2e obtained in Example 5 of this invention. 13 C10 NMR spectrum.
[0028] Figure 11 It is compound 2f obtained in Example 6 of this invention. 1 H NMR spectrum.
[0029] Figure 12 It is compound 2f obtained in Example 6 of this invention. 13 C10 NMR spectrum. Detailed Implementation
[0030] The technical solutions of the embodiments of the present invention will be clearly and completely described below with reference to the accompanying drawings. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.
[0031] Example 1 In this embodiment, cis-olefin compound 2a was synthesized by the following method, and the reaction equation is as follows: .
[0032] (1) Place a clean, dry Schlenk flask equipped with a clean magnetic stir bar into a glove box. Inside the glove box, add Pd(OAc)2 (0.56 mg, 0.05 mol%) and tetrabutylammonium perchlorate sequentially to the Schlenk flask. n -Bu4NClO4)(85.48 mg, 5 mol%); accurately weigh 1,2-bis(4-fluorophenyl)yne 1a (5 mmol) into the above Schlenk flask, then add 15 mL of toluene (Tol) and 5 mL of methanol (MeOH) as a mixed solvent, and then remove the Schlenk flask from the glove box; turn on the Schlenk flask, introduce H2 into the Schlenk flask, and carry out the reaction at room temperature and pressure.
[0033] (2) The reaction process was monitored by TLC and GC-MS. The reaction was considered complete when the reactant 1a was completely reacted. The volatile solvent in the reaction solution was removed by vacuum concentration using a rotary evaporator. Then, the concentrated reaction solution was purified by column chromatography using pure petroleum ether as the eluent to obtain cis-olefin compound 2a.
[0034] Compound 2a is a white solid with a yield of 76%.
[0035] The NMR spectrum of compound 2a is as follows: Figure 1 and Figure 2 As shown, the NMR data are: 1 H NMR (400 MHz, Chloroform-d) δ 7.17 (dd, J = 8.7, 5.6 Hz, 4H), 6.91 (t, J = 8.8 Hz, 4H), 6.52 (s, 2H); 13 C NMR (101 MHz, Chloroform- d ) δ 161.9 (d, J = 246.8 Hz), 133.0(d, J = 3.5 Hz), 130.5 (d, J = 7.9 Hz), 129.1, 115.3 (d, J = 21.3 Hz).
[0036] Example 2 In this embodiment, cis-olefin compound 2b was synthesized by the following method, and the reaction equation is as follows: .
[0037] (1) Place a clean, dry Schlenk flask equipped with a clean magnetic stir bar into a glove box. Inside the glove box, add Pd(OAc)2 (0.56 mg, 0.05 mol%) and tetrabutylammonium perchlorate sequentially to the Schlenk flask. n -Bu4NClO4)(85.48 mg, 5 mol%); accurately weigh 1-methyl-4-phenylacetylene 1b (5 mmol) into the above Schlenk flask, then add 15 mL of toluene (Tol) and 5 mL of methanol (MeOH) as a mixed solvent, and then remove the Schlenk flask from the glove box; turn on the Schlenk flask, introduce H2 into the Schlenk flask, and carry out the reaction at room temperature and pressure.
[0038] (2) The reaction process was monitored by TLC and GC-MS. The reaction was considered complete when the reactant 1b was completely reacted. The volatile solvent in the reaction solution was removed by vacuum concentration using a rotary evaporator. Then, the concentrated reaction solution was purified by column chromatography using pure petroleum ether as the eluent to obtain cis-olefin compound 2b.
[0039] Compound 2b is a colorless liquid with a yield of 81%.
[0040] The NMR spectrum of compound 2b is as follows: Figure 3 and Figure 4 As shown, the NMR data are: 1 H NMR (400 MHz, Chloroform- d ) δ 7.25 (dd, J = 8.2, 1.7 Hz, 2H), 7.23 – 7.15 (m, 3H), 7.16 –7.10 (m, 3H), 7.00 (d, J = 7.9 Hz, 2H), 6.53 (s, 2H), 2.28 (s, 3H); 13 C NMR (101MHz, Chloroform- d ) δ 137.6, 137.0, 134.4, 130.3, 129.7, 129.1, 129.0, 129.0,128.4, 127.1, 21.4.
[0041] Example 3 In this embodiment, cis-olefin compound 2c was synthesized by the following method, and the reaction equation is as follows: .
[0042] (1) Place a clean, dry Schlenk flask equipped with a clean magnetic stir bar into a glove box. Inside the glove box, add Pd(OAc)2 (0.56 mg, 0.05 mol%) and tetrabutylammonium perchlorate sequentially to the Schlenk flask. n -Bu4NClO4)(85.48 mg, 5 mol%); accurately weigh 1c (5 mmol) of 1-fluoro-4-phenylethynylbenzene into the above Schlenk flask, then add 15 mL of toluene (Tol) and 5 mL of methanol (MeOH) as a mixed solvent, and then remove the Schlenk flask from the glove box; turn on the Schlenk flask, introduce H2 into the Schlenk flask, and carry out the reaction at room temperature and pressure.
[0043] (2) The reaction process was monitored by TLC and GC-MS. The reaction was considered complete when the reactant 1c was completely reacted. The volatile solvent in the reaction solution was removed by vacuum concentration using a rotary evaporator. Then, the concentrated reaction solution was purified by column chromatography using pure petroleum ether as the eluent to obtain cis-olefin compound 2c.
[0044] Compound 2c is a colorless liquid with a yield of 75%.
[0045] The NMR spectrum of compound 2c is as follows Figure 5 and Figure 6 As shown, the NMR data are: 1 H NMR (400 MHz, Chloroform- d ) δ 7.27 – 7.16 (m, 7H), 6.90 (t, J = 8.8 Hz, 2H), 6.63 – 6.51 (m,2H); 13 C NMR (101 MHz, Chloroform- d ) δ 137.0, 133.2, 130.6, 130.5, 130.3,129.1, 128.8, 128.3, 127.2, 115.2 (d, J = 21.3 Hz).
[0046] Example 4 In this embodiment, the cis-olefin compound 2d was synthesized by the following method, and the reaction equation is as follows: .
[0047] (1) Place a clean, dry Schlenk flask equipped with a clean magnetic stir bar into a glove box. Inside the glove box, add Pd(OAc)2 (0.56 mg, 0.05 mol%) and tetrabutylammonium perchlorate sequentially to the Schlenk flask. n -Bu4NClO4)(85.48 mg, 5 mol%); accurately weigh 1,2-bis(4-methylbenzene)acetylene 1d (5 mmol) into the above Schlenk flask, then add 15 mL of toluene (Tol) and 5 mL of methanol (MeOH) as a mixed solvent, and then remove the Schlenk flask from the glove box; turn on the Schlenk flask, introduce H2 into the Schlenk flask, and carry out the reaction at room temperature and pressure.
[0048] (2) The reaction process was monitored by TLC and GC-MS. The reaction was considered complete when the raw material 1d was completely reacted. The volatile solvent in the reaction solution was removed by vacuum concentration using a rotary evaporator. Then, the concentrated reaction solution was purified by column chromatography using pure petroleum ether as the eluent to obtain cis-olefin compound 2d.
[0049] Compound 2d is a white solid with a yield of 92%.
[0050] The NMR spectrum of compound 2d is as follows Figure 7 and Figure 8 As shown, the NMR data are: 1 H NMR (400 MHz, Chloroform- d ) δ 7.17 – 7.13 (m, 4H), 7.01 (d, J = 8.0 Hz, 4H), 6.49 (s, 2H), 2.28 (s, 6H); 13 C NMR (101 MHz, Chloroform-d) δ 136.8, 134.6, 129.6, 129.0, 128.9, 21.3.
[0051] Example 5 In this embodiment, the cis-olefin compound 2e was synthesized by the following method, and the reaction equation is as follows: .
[0052] (1) Place a clean, dry Schlenk flask equipped with a clean magnetic stir bar into a glove box. Inside the glove box, add Pd(OAc)2 (0.56 mg, 0.05 mol%) and tetrabutylammonium perchlorate sequentially to the Schlenk flask. n-Bu4NClO4)(85.48 mg, 5 mol%); accurately weigh 1,3-dimethyl-5-phenylethynylbenzene 1e (5 mmol) into the above Schlenk flask, then add 15 mL of toluene (Tol) and 5 mL of methanol (MeOH) as a mixed solvent, and then remove the Schlenk flask from the glove box; turn on the Schlenk flask, introduce H2 into the Schlenk flask, and carry out the reaction at room temperature and pressure.
[0053] (2) The reaction process was monitored by TLC and GC-MS. The reaction was considered complete when the reactant 1e was completely reacted. The volatile solvent in the reaction solution was removed by vacuum concentration using a rotary evaporator. Then, the concentrated reaction solution was purified by column chromatography using pure petroleum ether as the eluent to obtain cis-olefin compound 2e.
[0054] Compound 2e is a white solid with a yield of 93%.
[0055] The NMR spectrum of compound 2e is as follows Figure 9 and Figure 10 As shown, the NMR data are: 1 H NMR (400 MHz, Chloroform- d ) δ 7.28 – 7.18 (m, 5H), 6.85 (d, J = 16.3 Hz, 3H), 6.54 (s, 2H), 2.20 (s, 6H); 13 C NMR (101 MHz, Chloroform- d ) δ 137.7, 137.4, 137.2, 130.5, 129.9, 128.9, 128.8, 128.1, 127.0, 126.6, 21.2.
[0056] Example 6 In this embodiment, the cis-olefin compound 2f was synthesized by the following method, and the reaction equation is as follows: .
[0057] (1) Place a clean, dry Schlenk flask equipped with a clean magnetic stir bar into a glove box. Inside the glove box, add Pd(OAc)2 (0.56 mg, 0.05 mol%) and tetrabutylammonium perchlorate sequentially to the Schlenk flask. n-Bu4NClO4)(85.48 mg, 5 mol%); accurately weigh 1-(2-phenylethynyl)-4-(trifluoromethoxy)benzene 1f (5 mmol) into the above Schlenk flask, then add 15 mL of toluene (Tol) and 5 mL of methanol (MeOH) as a mixed solvent, and then remove the Schlenk flask from the glove box; open the Schlenk flask valve, introduce H2 into the Schlenk flask, and carry out the reaction at room temperature and pressure.
[0058] (2) The reaction process was monitored by TLC and GC-MS. The reaction was considered complete when the reactant 1f was completely reacted. The volatile solvent in the reaction solution was removed by vacuum concentration using a rotary evaporator. Then, the concentrated reaction solution was purified by column chromatography using ethyl acetate / petroleum ether (ethyl acetate: petroleum ether = 1:100) as the eluent to obtain cis-olefin compound 2f.
[0059] Compound 2f is a white solid with a yield of 91%.
[0060] The NMR spectrum of compound 2f is as follows Figure 11 and Figure 12 As shown, the NMR data are: 1 H NMR (400 MHz, Chloroform- d ) δ 7.27 – 7.18 (m, 7H), 7.06 – 7.01 (m, 2H), 6.63 (d, J = 12.2Hz, 1H), 6.52 (d, J = 12.2 Hz, 1H); 13 C NMR (101 MHz, Chloroform- d ) δ 148.1,136.4, 131.2, 130.3, 128.9, 128.7, 128.4, 127.4, 121.8, 120.7, 119.3.
[0061] Although embodiments of the invention have been shown and described, it will be understood by those skilled in the art that various changes, modifications, substitutions and alterations can be made to these embodiments without departing from the principles and spirit of the invention, the scope of which is defined by the appended claims and their equivalents.
Claims
1. A method for preparing cis-olefins regulated by quaternary ammonium salts, characterized in that, Specifically, the following steps are included: (1) Under anhydrous and oxygen-free conditions, palladium salt catalyst, quaternary ammonium salt additive, solvent and diarylacetylene are added to the reaction vessel to obtain the reaction system; hydrogen atmosphere is introduced into the reaction system and then the reaction is stirred. (2) The reaction process was monitored by TLC and GC-MS. After the reaction was completed, the product was purified and separated to obtain the cis-olefin product.
2. The method for preparing cis-olefins regulated by quaternary ammonium salts according to claim 1, characterized in that, The structural formula of the diarylacetylene described in step (1) is as follows: , where R 1 For -H, -Me, -OMe, - i- Pr、- t One of -Bu, -F, -Cl, -Br, -COOMe, -CN, R 2 For -H, -Me, -OMe, - i- Pr、- t One of -Bu, -F, -Cl, -Br, -COOMe, -CN, R 1 and R 2 They can be the same or different.
3. The method for preparing cis-olefins regulated by quaternary ammonium salts according to claim 1, characterized in that, The palladium salt catalyst mentioned in step (1) is any one of palladium acetate, tetra(triphenylphosphine)palladium, tris(dibenzylideneacetone)palladium, palladium bromide, palladium iodide, palladium chloride, palladium trifluoroacetate, palladium on carbon, and palladium tetrafluoroborate tetraacetonitrile.
4. The method for preparing cis-olefins regulated by quaternary ammonium salts according to claim 1, characterized in that, The quaternary ammonium salt additive mentioned in step (1) is any one of tetrabutylammonium iodide, tetrabutylammonium bromide, tetrabutylammonium chloride, tetrabutylammonium hexafluorophosphate, tetrabutylammonium perchlorate, tetrabutylammonium acetate, and tetrabutylammonium fluoride.
5. The method for preparing cis-olefins regulated by quaternary ammonium salts according to claim 1, characterized in that, The solvent mentioned in step (1) is one or more of methanol, toluene, ethanol, isopropanol, tetrahydrofuran, acetonitrile, dioxane, dichloroethane and N,N-dimethylformamide.
6. The method for preparing cis-olefins regulated by quaternary ammonium salts according to claim 1, characterized in that, The molar ratio of palladium salt catalyst, quaternary ammonium salt additive and diarylacetylene in step (1) is 0.0001~0.001:0.01~0.3:
1.
7. The method for preparing cis-olefins regulated by quaternary ammonium salts according to claim 1, characterized in that, The concentration of diarylacetylene in the reaction system described in step (1) is 0.05~1 mol / L.
8. The method for preparing cis-olefins regulated by quaternary ammonium salts according to claim 1, characterized in that, In step (1), the pressure after introducing hydrogen atmosphere is 0.6-1.4 atm.
9. The method for preparing cis-olefins regulated by quaternary ammonium salts according to claim 1, characterized in that, The temperature of the stirring reaction in step (1) is 15-35°C. o C.