CN109020790B - Preparation method of 4-naphthenic acetophenone derivative - Google Patents
Preparation method of 4-naphthenic acetophenone derivative Download PDFInfo
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Abstract
The invention discloses a preparation method of a 4-naphthenic acetophenone derivative, and belongs to the technical field of organic compounds. The invention uses 2-substituted acetophenone derivatives or 3-substituted acetophenone derivatives as the starting material, the raw materials are easy to obtain and have a plurality of varieties; the method can be used for obtaining the p-cycloalkyl substituted acetophenone derivatives in one step, and the products have various types and can be directly used or used for other further reactions. The method has the advantages of simple reaction operation and post-treatment process, high yield, no generation of a large amount of metal salt, greenness, high atom economy and suitability for mass production.
Description
Technical Field
The invention relates to a preparation method of a 4-naphthenic acetophenone derivative, and belongs to the technical field of organic compounds.
Background
4-naphthenic acetophenone derivatives are an important medical intermediate. For example, compound a may be used synthetically to treat chikungunya fever caused by chikungunya virus (CHIKV). Both compounds B and C are physiologically active substances.
The Friedel-Crafts reaction is an important means of introducing alkyl functionality on aromatic rings. However, the acetyl group of acetophenone is an electron withdrawing group and the alkyl group is typically in the meta position to the acyl group.
Examples of para-alkylation reactions of amides are disclosed in org.Lett.2016,18, 2507-containing 2510, Angew.chem.2017,129,2793-2797 and Angew.chem.int.Ed.2017,56, 4853-containing 4857, respectively. However, the para-naphthenic reaction of acetophenone has not been reported.
In addition, the classical cross-coupling reaction is from (sp)2) C-M bond and alkyl radical, in situ construction (sp)2)C-(sp3) The C bond mode has been well developed, but the reaction system inevitably produces a large amount of metal salt. The method for directly constructing the C-C bond by utilizing C-H bond oxidative coupling can solve the problem, and meanwhile, the cross dehydrogenation coupling reaction also has the advantages of no need of substrate pre-functionalization, simple synthesis operation and the like. Therefore, the development of a synthesis method which has mild reaction conditions and wide application range and meets the requirements of green chemistry is very important.
Disclosure of Invention
In order to overcome the defects of lower yield, harsh reaction conditions and environmental unfriendliness of the 4-naphthenic acetophenone derivatives prepared by the prior art, the invention provides the method for preparing the 4-naphthenic acetophenone derivatives, which has the advantages of easily available raw materials, high yield, mild reaction conditions, good universality and environmental protection.
The first object of the present invention is to provide a method for preparing a 4-cycloalkylacetophenone derivative, comprising the steps of: taking a 2-substituted acetophenone derivative or a 3-substituted acetophenone derivative and cycloalkane as substrates, taking bis-hexafluoroacetylacetone nickel as a catalyst, and reacting at 120-160 ℃ under the action of oxalic acid diamantane, bis-trifluoromethanesulfonamide lithium and peroxy tert-butyl ether to prepare a 4-cycloalkylacetophenone derivative;
the 2-substituted acetophenone derivative or the 3-substituted acetophenone derivative is shown as the following structural general formula:
the 4-naphthenic acetophenone derivative is shown as the following structural general formula:
wherein R is selected from hydrogen, alkyl, alkoxy, acetyl, acetoxy or halogen; the substituent at the 4-position is: n is cycloalkyl or adamantyl equal to-1, 0,1, 2, 4, 6.
In one embodiment of the present invention, when n ═ 1, the substituent is cyclopentyl; when n is 0, the substituent is cyclohexane; when n is 1, the substituent is cycloheptyl; when n is 2, the substituent is cyclooctyl; when n is 4, the substituent is cyclodecyl; when n is 6, the substituent is cyclododecyl.
In one embodiment of the invention, the cycloalkane is cyclopentane, cyclohexane, cycloheptane, cyclooctane, cyclodecane, cyclododecane or adamantane.
In one embodiment of the invention, when the cycloalkane is solid, isopropyl acetate is used as the solvent.
In one embodiment of the present invention, the molar ratio of the acetophenone derivatives, nickel bis hexafluoroacetylacetonate, diamantadine oxalate, lithium bis trifluoromethanesulfonamide, and tert-butyl peroxy ether is 1 (0.05-0.2): (0.2-0.5): 1.5-2.5).
In one embodiment of the present invention, the molar ratio of the acetophenone derivatives, nickel bis hexafluoroacetylacetonate, diamantadine oxalate, lithium bis trifluoromethanesulfonamido and t-butyl peroxy ether is 1:0.1:0.1:0.4: 2.
In one embodiment of the invention, the reaction temperature is 140 ℃.
In one embodiment of the invention, after the reaction is finished, the 4-naphthenic acetophenone derivative is separated and purified by silica gel column chromatography.
In one embodiment of the invention, in the silica gel column chromatography, the elution solvent is a mixture of ethyl acetate and petroleum ether at a ratio of 1: 80-120.
The reaction process of the above technical scheme can be expressed as follows:
the second purpose of the invention is to provide the application of the method in the fields of medicine and chemical industry.
The invention has the beneficial effects that:
1. the invention uses 2-substituted acetophenone derivatives or 3-substituted acetophenone derivatives as the starting material, the raw materials are easy to obtain and have a plurality of varieties; the method can be used for obtaining the p-cycloalkyl substituted acetophenone derivatives in one step, and the products have various types and can be directly used or used for other further reactions.
2. The method has the advantages of simple reaction operation and post-treatment process, high yield, no generation of a large amount of metal salt, greenness, high atom economy and suitability for mass production.
Detailed Description
The present invention is further described below in conjunction with specific examples to enable those skilled in the art to better understand the present invention and to practice it, but the examples are not intended to limit the present invention.
Example 1: synthesis of 4-cyclohexylacetophenone
Acetophenone 1a (0.024g, 0.2mmol), nickel bis hexafluoroacetylacetonate (0.0094g, 10% mol), diamantadine oxalate (0.0071g, 10% mol), lithium bis trifluoromethanesulfonamido (0.024g, 40% mol), tert-butyl peroxy ether (0.101mL, 0.4mol) were weighed out and dissolved in 0.25mL cyclohexane. The mixture was heated to 140 ℃. After the reaction was completed, the crude product was purified by silica gel column chromatography (ethyl acetate: petroleum ether: 1:100) to obtain compound 3 a. The yield thereof was found to be 85%.
3a:1H NMR(400MHz,CDCl3)δ7.89(d,J＝8.4Hz,2H),7.29(d,J＝8.3Hz,2H),2.58(s,3H),2.57–2.52(m,1H),1.88-1.86(m,4H),1.77(d,J＝15.3Hz,1H),1.45-1.38(m,4H),1.32-1.26(m,1H).；13C NMR(101MHz,CDCl3)δ198.14,154.01,135.24,128.78,127.28,44.93,34.35,26.97,26.80,26.27.；HRMS Calcd forC14H18O[M+H+]:203.1436,Found:203.1434。
Example 2: synthesis of 3-methoxy-4-cyclohexylacetophenone
3-methoxyacetophenone 1b (0.03g, 0.2mmol), nickel bis hexafluoroacetylacetonate (0.0094g, 10% mol), diamantadine oxalate (0.0071g, 10% mol), lithium bis trifluoromethanesulfonamido (0.024g, 40% mol), tert-butyl peroxy ether (0.101mL, 0.4mol) were weighed out and dissolved in 0.25mL of cyclohexane 2 a. The mixture was heated to 140 ℃. After the reaction was completed, the crude product was purified by silica gel column chromatography (ethyl acetate: petroleum ether: 1:100) to obtain compound 3 b. The yield thereof was found to be 85%.
3b:1H NMR(400MHz,CDCl3)δ7.72(d,J＝8.3Hz,1H),7.61(d,J＝8.0Hz,1H),7.53(s,1H),3.88(s,3H),3.09-3.03(m,1H),2.63(s,3H),1.88-1.86(m,4H),1.77(d,J＝15.3Hz,1H),1.45-1.38(m,4H),1.32-1.26(m,1H).；13C NMR(101MHz,CDCl3)δ198.14,154.01,138.32,135.24,128.78,127.28,112.34,55.97,44.93,34.35,26.97,26.80,26.27.；HRMS Calcd for C15H20O[M+H+]:233.1542,Found:233.1586。
Example 3: synthesis of 3-methyl-4-cyclohexylacetophenone
3-methylacetophenone 1c (0.027g, 0.2mmol), nickel bis hexafluoroacetylacetonate (0.0094g, 10% mol), diamantadine oxalate (0.0071g, 10% mol), lithium bis trifluoromethanesulfonamido (0.024g, 40% mol), tert-butyl peroxy ether (0.101mL, 0.4mol) were weighed out and dissolved in 0.25mL cyclohexane 2 a. The mixture was heated to 140 ℃. After the reaction was completed, the crude product was purified by silica gel column chromatography (ethyl acetate: petroleum ether: 1:100) to obtain compound 3 c. The yield thereof was found to be 68%.
3c:1H NMR(400MHz,CDCl3)δ7.72(d,J＝8.3Hz,1H),7.61(d,J＝8.0Hz,1H),7.53(s,1H),3.09-3.03(m,1H),2.63(s,3H),2.51(s,3H),1.88-1.86(m,4H),1.77(d,J＝15.3Hz,1H),1.45-1.38(m,4H),1.32-1.26(m,1H).；13C NMR(101MHz,CDCl3)δ198.14,154.01,138.32,135.24,128.78,127.28,112.34,44.93,34.35,26.97,26.80,26.27,24.58；HRMS Calcd for C15H20O[M+H+]:217.1514,Found:217.1505。
Example 4: synthesis of 3-chloro-4-cyclohexylacetophenone
3-Chloroacetophenone 1d (0.031g, 0.2mmol), nickel bis hexafluoroacetylacetonate (0.0094g, 10% mol), diamantadine oxalate (0.0071g, 10% mol), lithium bis trifluoromethanesulfonamide (0.024g, 40% mol), tert-butyl peroxy ether (0.101mL, 0.4mol) were weighed out and dissolved in 0.25mL cyclohexane 2 a. The mixture was heated to 140 ℃. After the reaction was completed, the crude product was purified by silica gel column chromatography (ethyl acetate: petroleum ether: 1:100) to obtain compound 3 d. The yield thereof was found to be 62%.
3d:1H NMR(400MHz,CDCl3)δ7.92(s,1H),7.80(d,J＝8.1Hz,1H),7.36(d,J＝8.1Hz,1H),3.08-3.02(m,1H),2.57(s,3H),1.89-1.85(m,4H),1.79(d,J＝10.0Hz,1H),1.47-1.30(m,5H).；13C NMR(101MHz,CDCl3)δ196.92,150.45,136.17,134.31,129.70,127.59,127.04,41.05,33.05,26.93,26.79,26.34.；HRMSCalcd for C14H17ClO[M+H+]:237.1046,Found:237.1080。
Example 5: synthesis of 3-bromo-4-cyclohexylacetophenone
3-bromoacetophenone 1e (0.039g, 0.2mmol), nickel bis hexafluoroacetylacetonate (0.0094g, 10% mol), diamantadine oxalate (0.0071g, 10% mol), lithium bis trifluoromethanesulfonamido (0.024g, 40% mol), tert-butyl peroxy ether (0.101mL, 0.4mol) were weighed out and dissolved in 0.25mL cyclohexane 2 a. The mixture was heated to 140 ℃. After the reaction was completed, the crude product was purified by silica gel column chromatography (ethyl acetate: petroleum ether: 1:100) to obtain compound 3 e. The yield thereof was found to be 46%.
3e:1H NMR(400MHz,CDCl3)δ7.91(s,1H),7.82(d,J＝8.1Hz,1H),7.40(d,J＝8.1Hz,1H),3.09-3.03(m,1H),2.58(s,3H),1.89-1.85(m,4H),1.79(d,J＝10.0Hz,1H),1.47-1.30(m,5H).；13C NMR(101MHz,CDCl3)δ196.92,151.45,137.17,134.31,129.70,128.59,127.04,41.05,33.05,26.93,26.79,25.34.；HRMS Calcd for C14H17BrO[M+H+]:281.0541,Found:281.0565。
Example 6: synthesis of 3-acetoxyl-4-cyclohexyl acetophenone
3-Acetooxyacetophenone 1f (0.036g, 0.2mmol), nickel bis hexafluoroacetylacetonate (0.0094g, 10% mol), diamantadine oxalate (0.0071g, 10% mol), lithium bis trifluoromethanesulfonamido (0.024g, 40% mol), tert-butyl peroxy ether (0.101mL, 0.4mol) were weighed out and dissolved in 0.25mL of cyclohexane 2 a. The mixture was heated to 140 ℃. After the reaction was completed, the crude product was purified by silica gel column chromatography (ethyl acetate: petroleum ether: 1:100) to obtain compound 3 f. The yield thereof was found to be 53%.
3f:1H NMR(400MHz,CDCl3)δ7.80(d,J＝8.1Hz,1H),7.59(s,1H),7.39(d,J＝8.1Hz,1H),2.66-2.62(m,1H),2.56(s,3H),2.35(s,3H),1.86-1.75(m,5H),1.45-1.32(m,5H).；13C NMR(101MHz,CDCl3)δ196.27,194.14,161.46,157.65,139.85,136.04,127.41,123.73,114.44,36.93,32.28,26.18,26.09,25.54.；HRMS Calcd for C16H20O3[M+H+]:261.1491,Found:261.1471。
Example 7: synthesis of 3-acetyl-4-cyclohexylacetophenone
3-Acetoacetophenone 1g (0.032g, 0.2mmol), nickel bis hexafluoroacetylacetonate (0.0094g, 10% mol), diamantadine oxalate (0.0071g, 10% mol), lithium bis trifluoromethanesulfonamido (0.024g, 40% mol), tert-butyl peroxy ether (0.101mL, 0.4mol) were weighed out and dissolved in 0.25mL cyclohexane 2 a. The mixture was heated to 140 ℃. After the reaction was completed, the crude product was purified by silica gel column chromatography (ethyl acetate: petroleum ether: 1:100) to obtain 3g of a compound. The yield thereof was found to be 32%.
3g:1H NMR(400MHz,CDCl3)δ7.76(d,J＝8.0Hz,1H),7.56(s,1H),7.24(d,J＝7.9Hz,1H),2.57-2.53(m,1H),2.54(s,3H),2.51(s,3H),1.89-1.78(m,5H),1.41-1.27(m,5H).；13C NMR(101MHz,CDCl3)δ194.67,192.18,161.56,157.56,139.58,136.40,127.14,123.37,114.42,36.39,36.21,32.28,26.81,26.90,25.45.；HRMS Calcd for C16H20O2[M+H+]:245.1542,Found:245.1551。
Example 8: synthesis of 2-methoxy-4-cyclohexylacetophenone
2-methoxyacetophenone was weighed out for 1h (0.030g, 0.2mmol), nickel bis hexafluoroacetylacetonate (0.0094g, 10% mol), diamantadine oxalate (0.0071g, 10% mol), lithium bis trifluoromethanesulfonamide (0.024g, 40% mol), tert-butyl peroxy-ether (0.101mL, 0.4mol) dissolved in 0.25mL of cyclohexane 2 a. The mixture was heated to 140 ℃. After the reaction was completed, the crude product was purified by silica gel column chromatography (ethyl acetate: petroleum ether: 1:100) to obtain compound 3 h. The yield thereof was found to be 70%.
3h:1H NMR(400MHz,CDCl3)δ7.67(d,J＝7.9Hz,1H),7.10(d,J＝8.1Hz,1H),7.08(s,1H),3.89(s,3H),2.54(s,3H),2.59–2.46(m,1H),1.87-1.84(m,4H),1.76(d,J＝14.0Hz,1H),1.47–1.30(m,5H).；13C NMR(101MHz,CDCl3)δ195.39,156.13,144.13,135.18,127.27,124.56,116.57,55.60,36.39,32.75,26.48,26.90,25.62.；HRMS Calcd for C15H20O[M+H+]:233.1463,Found:233.1424。
Example 9: synthesis of 2-methyl-4-cyclohexylacetophenone
2-methylacetophenone 1i (0.030g, 0.2mmol), nickel bis hexafluoroacetylacetonate (0.0094g, 10% mol), diamantadine oxalate (0.0071g, 10% mol), lithium bis trifluoromethanesulfonamido (0.024g, 40% mol), tert-butyl peroxy ether (0.101mL, 0.4mol) were weighed out and dissolved in 0.25mL of cyclohexane 2 a. The mixture was heated to 140 ℃. After the reaction was completed, the crude product was purified by silica gel column chromatography (ethyl acetate: petroleum ether: 1:100) to obtain compound 3 i. The yield thereof was found to be 68%.
3i:1H NMR(400MHz,CDCl3)δ7.67(d,J＝7.9Hz,1H),7.10(d,J＝8.1Hz,1H),7.08(s,1H),2.56(s,3H),2.54(s,3H),2.59–2.46(m,1H),1.87-1.84(m,4H),1.76(d,J＝14.0Hz,1H),1.47–1.30(m,5H).；13C NMR(101MHz,CDCl3)δ195.39,156.13,144.13,135.18,127.27,124.56,116.57,36.39,32.75,26.48,26.90,25.62,20.47.；HRMS Calcd for C15H20O[M+H+]:217.1592,Found:217.1571。
Example 10: synthesis of 2-chloro-4-cyclohexylacetophenone
2-Chloroacetophenone 1j (0.031g, 0.2mmol), nickel bis hexafluoroacetylacetonate (0.0094g, 10% mol), diamantadine oxalate (0.0071g, 10% mol), lithium bis trifluoromethanesulfonamide (0.024g, 40% mol), tert-butyl peroxy ether (0.101mL, 0.4mol) were weighed out and dissolved in 0.25mL cyclohexane 2 a. The mixture was heated to 140 ℃. After the reaction was completed, the crude product was purified by silica gel column chromatography (ethyl acetate: petroleum ether: 1:100) to obtain compound 3 j. The yield thereof was found to be 33%.
3j:1H NMR(400MHz,CDCl3)δ7.68(s,1H),7.62–7.54(m,2H),3.05-3.02(m,1H),2.59(s,3H),1.89-1.85(m,4H),1.77(d,J＝10.9Hz,1H),1.45–1.28(m,5H).；13C NMR(101MHz,CDCl3)δ199.77,141.56,136.39,131.62,129.49,127.87,124.26,36.92,32.28,26.19,26.10,25.65.；HRMS Calcd for C14H17ClO[M+H+]:237.1046,Found:237.1021。
Example 11: synthesis of 2, 5-dichloro-4-cyclohexylacetophenone
2, 5-Dichloroacetophenone 1k (0.038g, 0.2mmol), nickel bis hexafluoroacetylacetonate (0.0094g, 10% mol), diamantadine oxalate (0.0071g, 10% mol), lithium bis trifluoromethanesulfonamido (0.024g, 40% mol), tert-butyl peroxy ether (0.101mL, 0.4mol) were weighed out and dissolved in 0.25mL cyclohexane 2 a. The mixture was heated to 140 ℃. After the reaction was completed, the crude product was purified by silica gel column chromatography (ethyl acetate: petroleum ether: 1:100) to obtain compound 3 k. The yield thereof was found to be 38%.
3k:1H NMR(400MHz,CDCl3)δ7.72(s,1H),7.55(s,1H),2.68-2.62(m,1H),2.55(s,3H),1.81-1.75(m,4H),1.72(d,J＝11.0Hz,1H),1.43-1.26(m,5H).；13CNMR(101MHz,CDCl3)δ197.42,145.26,137.81,132.56,129.87,128.52,119.20,36.37,32.80,26.50,26.04,25.31.；HRMS Calcd for C14H16Cl2O[M+H+]:271.0656,Found:271.0670。
Example 12: synthesis of 2, 5-dimethoxy-4-cyclohexylacetophenone
2, 5-dimethoxyacetophenone 1l (0.036g, 0.2mmol), nickel bis hexafluoroacetylacetonate (0.0094g, 10% mol), diamantadine oxalate (0.0071g, 10% mol), lithium bis trifluoromethanesulfonamido (0.024g, 40% mol), tert-butyl peroxy ether (0.101mL, 0.4mol) were weighed out and dissolved in 0.25mL cyclohexane 2 a. The mixture was heated to 140 ℃. After the reaction was completed, the crude product was purified by silica gel column chromatography (ethyl acetate: petroleum ether: 1:100) to obtain 3l of a compound. The yield thereof was found to be 45%.
3l:1H NMR(400MHz,CDCl3)δ7.30(s,1H),6.82(s,1H),3.88(s,3H),3.81(s,3H),3.00-2.94(m,1H),2.61(s,3H),1.85-1.82(m,4H),1.77(d,J＝12.7Hz,1H),1.48–1.29(m,5H).；13C NMR(101MHz,CDCl3)δ197.03,152.08,148.39,137.98,124.47,121.80,111.53,57.51,56.86,37.80,34.92,26.60,26.00 25,25.41.；HRMS Calcd for C16H22O3[M+H+]:263.1647,Found:263.1651。
Example 13: synthesis of 2-bromo-5-methoxy-4-cyclohexylacetophenone
2-bromo-5-methoxyacetophenone 1m (0.044g, 0.2mmol), nickel bis hexafluoroacetylacetonate (0.0094g, 10% mol), diamantadine oxalate (0.0071g, 10% mol), lithium bis trifluoromethanesulfonamide (0.024g, 40% mol), tert-butyl peroxy ether (0.101mL, 0.4mol) were weighed out and dissolved in 0.25mL cyclohexane 2 a. The mixture was heated to 140 ℃. After the reaction was completed, the crude product was purified by silica gel column chromatography (ethyl acetate: petroleum ether: 1:100) to obtain compound 3 m. The yield thereof was found to be 53%.
3m:1H NMR(400MHz,CDCl3)δ7.45(s,1H),7.30(s,1H),3.83(s,3H),2.74-2.70(m,1H),2.51(s,3H),1.87-1.85(m,5H),1.56-1.48(m,5H).；13C NMR(101MHz,CDCl3)δ199.82,155.08,139.13,138.51,132.27,114.80,113.63,56.16,36.80,34.90,28.60,26.48,25.50.；HRMS Calcd for C15H29BrO2[M+H+]:311.0647,Found:311.0630。
Example 14: synthesis of 4-cyclopentylacetophenone
Acetophenone 1a (0.024g, 0.2mmol), nickel bis hexafluoroacetylacetonate (0.0094g, 10% mol), diamantadine oxalate (0.0071g, 10% mol), lithium bis trifluoromethanesulfonamide (0.024g, 40% mol), tert-butyl peroxy ether (0.101mL, 0.4mol) were weighed out and dissolved in 0.25mL of cyclopentane 2 b. The mixture was heated to 140 ℃. After the reaction was completed, the crude product was purified by silica gel column chromatography (ethyl acetate: petroleum ether: 1:100) to obtain compound 3 n. The yield thereof was found to be 45%.
3n:1H NMR(400MHz,CDCl3)δ7.84(d,J＝8.2Hz,2H),7.28(d,J＝8.1Hz,2H),2.57(s,3H),2.57–2.52(m,1H),2.25-2.20(m,2H),1.91-1.77(m,6H).；13CNMR(101MHz,CDCl3)δ198.13,154.00,135.24,128.77,127.27,34.34,26.95,26.78,26.10.；HRMS Calcd for C13H16O[M+H+]:189.1279,Found:189.1281。
Example 15: synthesis of 4-cycloheptylacetophenone
Acetophenone 1a (0.024g, 0.2mmol), nickel bis hexafluoroacetylacetonate (0.0094g, 10% mol), diamantadine oxalate (0.0071g, 10% mol), lithium bis trifluoromethanesulfonamido (0.024g, 40% mol), tert-butyl peroxy ether (0.101mL, 0.4mol) were weighed out and dissolved in 0.25mL cycloheptane 2 c. The mixture was heated to 140 ℃. After the reaction was completed, the crude product was purified by silica gel column chromatography (ethyl acetate: petroleum ether: 1:100) to obtain compound 3 o. The yield thereof was found to be 40%.
3o:1H NMR(400MHz,CDCl3)δ7.88(d,J＝8.5Hz,2H),7.32(d,J＝8.4Hz,2H),2.57(s,3H),2.62–2.58(m,1H),2.18-2.12(m,4H),1.87-1.75(m,8H).；13CNMR(101MHz,CDCl3)δ197.10,146.00,133.92,128.62,128.02,46.72,36.93,29.32,26.60,26.45.；HRMS Calcd for C15H20O[M+H+]:217.1592,Found:217.1581。
Example 16: synthesis of 4-cyclooctylacetophenone
Acetophenone 1a (0.024g, 0.2mmol), cyclooctane 2d (0.06g, 0.6mmol), nickel bis hexafluoroacetylacetonate (0.0094g, 10% mol), diamantadine oxalate (0.0071g, 10% mol), lithium bis trifluoromethanesulfonylamide (0.024g, 40% mol), tert-butyl peroxy ether (0.101mL, 0.4mol) were weighed out and dissolved in 0.25mL of cyclohexane 2 a. The mixture was heated to 140 ℃. After the reaction was completed, the crude product was purified by silica gel column chromatography (ethyl acetate: petroleum ether: 1:100) to obtain compound 3 p. The yield thereof was found to be 36%.
3p:1H NMR(400MHz,CDCl3)δ7.86(d,J＝8.4Hz,2H),7.30(d,J＝8.3Hz,2H),2.72–2.68(m,1H),2.56(s,3H),2.32-2.28(m,4H),1.97-1.85(m,10H).；13CNMR(101MHz,CDCl3)δ197.00,146.33,134.26,128.25,128.00,47.02,36.86,29.51,26.98,26.45,25.43.；HRMS Calcd for C16H22O[M+H+]:231.1749,Found:231.1761。
Example 17: synthesis of 4-cyclododecylacetophenone
Acetophenone 1a (0.024g, 0.2mmol), cyclododecane 2e (0.1g, 0.6mmol), bis-hexafluoroacetylacetonatonickel (0.0094g, 10% mol), diamantadine oxalate (0.0071g, 10% mol), lithium bis-trifluoromethanesulfonylamide (0.024g, 40% mol), tert-butyl peroxy ether (0.101mL, 0.4mol) were weighed out in 0.25mL of isopropyl acetate. The mixture was heated to 140 ℃. After the reaction was completed, the crude product was purified by silica gel column chromatography (ethyl acetate: petroleum ether: 1:100) to obtain compound 3 q. The yield thereof was found to be 34%.
3q:1H NMR(400MHz,CDCl3)δ7.91(d,J＝8.3Hz,2H),7.35(d,J＝8.1Hz,2H),2.71–2.67(m,1H),2.57(s,3H),2.31-2.27(m,4H),1.96-1.84(m,18H).；13CNMR(101MHz,CDCl3)δ198.21,146.32,134.25,128.52,128.31,38.82,37.76,26.65,24.62,24.58,24.24.；HRMS Calcd for C20H30O[M+H+]:287.2375,Found:287.2392。
Example 18: synthesis of 4-adamantaneacetophenone
Acetophenone 1a (0.024g, 0.2mmol), adamantane 2g (0.08g, 0.6mmol), nickel bis hexafluoroacetylacetonate (0.0094g, 10% mol), diamantane oxalate (0.0071g, 10% mol), lithium bis trifluoromethanesulfonylamide (0.024g, 40% mol), tert-butyl peroxy ether (0.101mL, 0.4mol) were weighed out in 0.25mL isopropyl acetate. The mixture was heated to 140 ℃. After the reaction was completed, the crude product was purified by silica gel column chromatography (ethyl acetate: petroleum ether: 1:100) to obtain compound 3 r. The yield thereof was found to be 41%.
3r:1H NMR(400MHz,CDCl3)δ7.91(d,J＝8.6Hz,2H),7.45(d,J＝8.6Hz,2H),2.59(s,3H),2.14-2.12(m,3H),1.93-1.92(d,J＝2.6Hz,5H),1.83-1.74(m,7H).；13C NMR(101MHz,CDCl3):δ198.42,144.17,132.12,127.53,126.85,42.71,39.45,37.04,29.23,26.68.；HRMS Calcd for C18H22O[M+H+]:255.1749,Found:255.1761。
The above-mentioned embodiments are merely preferred embodiments for fully illustrating the present invention, and the scope of the present invention is not limited thereto. The equivalent substitution or change made by the technical personnel in the technical field on the basis of the invention is all within the protection scope of the invention. The protection scope of the invention is subject to the claims.
Claims (8)
1. A preparation method of a 4-naphthenic acetophenone derivative is characterized by comprising the following steps: 2-substituted acetophenone derivatives or 3-substituted acetophenone derivatives and cycloalkanes are taken as substrates, bis-hexafluoroacetylacetone nickel is taken as a catalyst, and under the action of oxalic acid diamantane, bis-trifluoromethanesulfonamide lithium and peroxy tert-butyl ether, the reaction temperature is 120-160 DEG CoReaction under the condition of C to preparePreparing 4-naphthenic acetophenone derivatives;
the 2-substituted acetophenone derivative or the 3-substituted acetophenone derivative is shown as the following structural general formula:
wherein R is selected from hydrogen, alkyl, alkoxy, acetyl, acetoxy or halogen;
the 4-position substituent in the 4-naphthenic acetophenone derivative is cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecanyl, cyclododecyl or adamantyl.
2. The method according to claim 1, wherein the cycloalkane is cyclopentane, cyclohexane, cycloheptane, cyclooctane, cyclodecane, cyclododecane or adamantane.
3. The process according to claim 1, wherein isopropyl acetate is used as a solvent when the cycloalkane is a solid.
4. The method according to claim 1, wherein the molar ratio of the acetophenone derivatives, nickel bis hexafluoroacetylacetonate, diamantane oxalate, lithium bis trifluoromethanesulfonamide, and t-butyl peroxy ether is 1 (0.05-0.2): (0.2-0.5): 1.5-2.5).
5. The process according to claim 1, wherein the molar ratio of the acetophenone derivatives, nickel bis hexafluoroacetylacetonate, diamantane oxalate, lithium bis trifluoromethanesulfonamide and t-butyl peroxy ether is 1:0.1:0.1:0.4: 2.
6. The method of claim 1, wherein the reaction temperature is 140 ℃oC。
7. The process according to claim 1, wherein the 4-cycloalkylacetophenone derivative is isolated and purified by silica gel column chromatography after the completion of the reaction.
8. The preparation method according to claim 7, wherein the elution solvent is a mixture of ethyl acetate and petroleum ether at a ratio of 1:80-120 in the silica gel column chromatography.
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