A method for synthesizing naphthalene compounds
By using the method of combining the substrate of carbon-carbon triple-bonded substituted groups with hydroxyl groups, the problems of difficulty in synthesizing naphthalene ring skeleton in the prior art are solved, and efficient naphthalene ring skeleton synthesis is achieved without the need for precious metal catalysts.
Patent Information
- Application Number
- CN202211673168.X
- Authority / Receiving Office
- CN · China
- Patent Type
- Patents(China)
- Current Assignee / Owner
- Filing Date
- 2022-12-26
- Publication Date
- 2025-03-14
- Estimated Expiration
- 2042-12-26
AI Technical Summary
In the prior art, the method for synthesizing a naphthalene ring backbone has problems such as difficulty in forming the first C-C bond, long reaction time and low yield.
The substrate of carbon-carbon triple bond substituted groups is used to synthesize the naphthalene ring skeleton with hydroxyl groups. The product is obtained by mixing the compound, solvent and accelerator in a pressure-resistant tube, and an oil bath reaction is carried out under an air atmosphere, and water is added and extracted and purified.
It effectively reduces the difficulty of the reaction, improves the reaction efficiency, and does not require precious metal catalysts, and the reaction conditions are mild.
Smart Images
Figure CN116041126B_ABST
Abstract
Description
Technical Field
[0001] The invention belongs to the technical field of naphthalene synthesis, and particularly relates to a method for synthesizing a naphthalene compound. Background Art
[0002] Naphthalene is the simplest condensed aromatic hydrocarbon and an attractive structural skeleton that is widely present in various biologically active natural products. Common naphthalene compounds include nafcillin, Cambinol, naproxen, and velpatasvir. Among them, nafcillin has been used as an antimicrobial drug due to its satisfactory antimicrobial effect. In addition, they also play an important role in nanotechnology, electronic materials, and supramolecular chemistry. Therefore, how to simply and efficiently construct a naphthalene ring skeleton from simple and readily available raw materials has always been one of the important topics of common concern in the field of organic and drug synthesis.
[0003] In the past few years, synthetic chemists have developed several efficient methods for the construction of naphthalene ring skeletons. Our attention has been attracted by those Lewis acid-catalyzed intermolecular cyclizations using alkynes as partners because of their operational simplicity and readily available substrates. The Lewis acid-catalyzed intermolecular addition between the (2-phenylethyl)carbonyl group and the alkyne initially forms the first C-C bond. Then, the in situ formed alkenyl carbocation undergoes an intramolecular Friedel-Crafts reaction to generate the naphthalene product. In these tandem methods, two new C-C bonds and a new benzene ring are generated in one pot. However, some of them suffer from long reaction times and low yields due to the difficulty in the formation of the first C-C bond. Summary of the invention
[0004] In view of the problems in the prior art, the present invention provides a method for synthesizing a naphthalene compound, which uses a substrate with a carbon-carbon triple bond substituent group in combination with a hydroxyl group to synthesize a naphthalene ring skeleton.
[0005] In order to achieve the above technical objectives, the technical solution of the present invention is:
[0006] A method for synthesizing a naphthalene compound, comprising:
[0007]
[0008] Wherein, X is a substituent, preferably a hydrogen group or a halogen, and R1 is an aromatic ring or an aromatic heterocycle, preferably a phenyl group or a thiophene group.
[0009] The accelerator is one of Tf2O, TfOH, and TsOH·H2O, preferably Tf2O.
[0010] The solvent is chloroform or DCM, preferably chloroform.
[0011] The temperature is 25-100°C, preferably 80°C.
[0012] The reaction time is 0.5-4h, preferably 3h.
[0013] Further, the specific steps of the method for synthesizing naphthalene compounds include:
[0014] In a pressure tube, compound 1 (0.2 mmol, 1.0 equiv.), solvent (1.5 mL) and promoter (0.1 mmol, 0.5 equiv.) were mixed and reacted in an oil bath under air atmosphere. After the reaction, 5 mL of water was added to the reaction mixture and extracted with 12 mL of ethyl acetate three times, and the organic layer was collected; the organic layer was dried over Na2SO4 and evaporated under reduced pressure, and then purified by silica gel column chromatography using petroleum ether as eluent to obtain product 2.
[0015] The solvent used was chloroform.
[0016] The accelerator is trifluoromethanesulfonic anhydride.
[0017] The temperature of the oil bath reaction was 80°C.
[0018] The oil bath reaction time is 3 h.
[0019] It can be seen from the above description that the present invention has the following advantages:
[0020] The present invention solves the defects of the existing process and adopts a substrate with a carbon-carbon triple bond substituted group in combination with a hydroxyl group for the first time to synthesize a naphthalene ring skeleton, which not only effectively reduces the difficulty of the reaction and improves the reaction efficiency, but also does not require a noble metal catalyst and has mild reaction conditions. BRIEF DESCRIPTION OF THE DRAWINGS
[0021] Figure 1 is the H NMR spectrum of 1-methyl-3-phenylnaphthalene in Example 1 of the present invention;
[0022] Figure 2 is the NMR carbon spectrum of 1-methyl-3-phenylnaphthalene in Example 1 of the present invention;
[0023] Figure 3 is the H NMR spectrum of 2-(4-methylnaphthalene-2-yl)thiophene in Example 2 of the present invention;
[0024] Figure 4 is the NMR carbon spectrum of 2-(4-methylnaphthalene-2-yl)thiophene in Example 2 of the present invention;
[0025] Figure 5 is the H NMR spectrum of 6-chloro-1-methyl-3-phenylnaphthalene in Example 3 of the present invention;
[0026] Figure 6It is the NMR carbon spectrum of 6-chloro-1-methyl-3-phenylnaphthalene in Example 3 of the present invention. DETAILED DESCRIPTION
[0027] Combined with Figure 1 To Attachment Figure 6 , describes in detail the specific embodiments of the present invention, but does not limit the claims of the present invention.
[0028] A method for synthesizing naphthalene compounds, the general reaction formula is:
[0029]
[0030] Wherein, X is a substituent, preferably a hydrogen group or a halogen, and R1 is an aromatic ring or an aromatic heterocycle, preferably a phenyl group or a thiophene group.
[0031] The specific steps include:
[0032] In a pressure tube, compound 1 (0.2 mmol, 1.0 equiv.), solvent (1.5 mL) and promoter (0.1 mmol, 0.5 equiv.) were mixed and reacted in an oil bath under air atmosphere. After the reaction, 5 mL of water was added to the reaction mixture and extracted with 12 mL of ethyl acetate three times, and the organic layer was collected. The organic layer was dried over Na2SO4 and then evaporated under reduced pressure, and then purified by silica gel column chromatography using petroleum ether as an eluent to obtain product 2.
[0033] s1, temperature selection:
[0034] According to the above specific steps, the reaction is carried out, and the reaction formula is as follows:
[0035]
[0036] The reaction conditions include: 1a (0.1 mmol, 1.0 equiv) and Tf2O (0.05 mmol, 0.5 equiv) were reacted in CHCl3 (1.5 mL) under air atmosphere at different temperatures for 3 hours. The reaction data are as follows:
[0037] Temperature / ℃ 2a Yield / % 1 25 19 2 40 41 3 60 55 4 80 75 5 100 64
[0038] It can be seen from the above data that the yield of product 2 is the highest at 80°C, that is, the temperature of the oil bath reaction is preferably 80°C.
[0039] s2, reaction time selection
[0040] The reaction was carried out according to the above specific steps. The reaction formula was the same as s1. The reaction conditions included: 1a (0.1 mmol, 1.0 equiv) and Tf2O (0.05 mmol, 0.5 equiv) were reacted in CHCl3 (1.5 mL) under air atmosphere at 80°C for different times. The reaction data are as follows:
[0041] Time / h 2a Yield / % 1 0.5 45 2 1 53 3 2 60 4 3 75 5 4 66
[0042] It can be seen from the above data that the yield of product 2 is the highest at 3 h, that is, the time of oil bath reaction is preferably 3 h.
[0043] s3, choice of solvent:
[0044] The reaction was carried out according to the above specific steps. The reaction formula was the same as s1. The reaction conditions included: 1a (0.1 mmol, 1.0 equiv) and Tf2O (0.05 mmol, 0.5 equiv) were reacted in different solvents (1.5 mL) under air atmosphere at 80°C for 3 h. The reaction data are as follows:
[0045] Solvents 2a Yield / % 1 <![CDATA[CHCl3]]> 75 2 DCM 24 3 DMSO 0 4 DMF 0 5 THF 0
[0046] From the above data, it can be seen that product 2a is obtained under CHCl3 and DCM, and the yield of CHCl3 is higher, that is, the solvent for this reaction is preferably CHCl3.
[0047] s4, choice of accelerator
[0048] The reaction was carried out according to the above specific steps. The reaction formula was the same as s1. The reaction conditions included: 1a (0.1 mmol, 1.0 equiv) and the promoter were reacted in CHCl3 (1.5 mL) under air atmosphere at 80°C for 3 h. The reaction data are as follows:
[0049]
[0050]
[0051] It can be seen from the above data that the yield of product 2a is higher at 0.5 equiv Tf2O, that is, the promoter of this reaction is preferably 0.5 equiv Tf2O.
[0052] Example 1
[0053] Preparation of 1-methyl-3-phenylnaphthalene
[0054] The molecular formula of the 1-methyl-3-phenylnaphthalene is:
[0055]
[0056] The specific synthesis steps of the 1-methyl-3-phenylnaphthalene include:
[0057]
[0058] In a pressure tube, 2-(2-(phenylethynyl)phenyl)propan-2-ol (0.2mmol, 1.0equiv.), chloroform (1.5mL) and Tf2O (0.1mmol, 0.5equiv.) were mixed and reacted in an oil bath at 80°C for 3h under air atmosphere. After the reaction, 5mL of water was added to the reaction mixture and extracted with 12mL of ethyl acetate three times, and the organic layer was collected. The organic layer was dried over Na2SO4 and then evaporated under reduced pressure, and then purified by silica gel column chromatography using petroleum ether as eluent to obtain product 2, i.e., 1-methyl-3-phenylnaphthalene, with a yield of 75%.
[0059] The NMR of 1-methyl-3-phenylnaphthalene prepared in this example is shown in the attached Figure 1 and attached Figure 2 As shown in the attached Figure 1 As shown, 1 H NMR (400 MHz, CDCl3) δ8.08–8.00 (m, 1H), 7.97–7.88 (m, 2H), 7.79–7.71 (m, 2H), 7.63 (s, 1H), 7.60–7.44 (m, 4H), 7.44–7.36 (m, 1H), 2.79 (s, 3H); as attached Figure 2 As shown, 13 C NMR (101MHz, CDCl3) δ141.25,138.21,134.87,133.88,131.86,128.87,128.83,127.42,127.29,126.38,126.03,125.83,124.27,124.03,19.58.
[0060] Example 2
[0061] Preparation of 2-(4-methylnaphthalen-2-yl)thiophene
[0062] The molecular formula of the 2-(4-methylnaphthalene-2-yl)thiophene is:
[0063]
[0064] The specific synthesis steps of the 2-(4-methylnaphthalene-2-yl)thiophene include:
[0065]
[0066] In a pressure tube, 2-(2-(thienylethynyl)phenyl)propan-2-ol (0.2mmol, 1.0equiv.), chloroform (1.5mL) and Tf2O (0.1mmol, 0.5equiv.) were mixed and reacted in an oil bath at 80°C for 3h under air atmosphere. After the reaction, 5mL of water was added to the reaction mixture and extracted with 12mL of ethyl acetate three times, and the organic layer was collected. The organic layer was dried over Na2SO4 and then evaporated under reduced pressure, and then purified by silica gel column chromatography using petroleum ether as an eluent to obtain product 2, i.e., 2-(4-methylnaphthalene-2-yl)thiophene, with a yield of 61%.
[0067] The NMR of 2-(4-methylnaphthalen-2-yl)thiophene prepared in this example is shown in the attached Figure 3 and attached Figure 4 As shown in the attached Figure 3 As shown, 1 H NMR(500MHz, CDCl3)δ7.98(ddt,J=6.8,4.3,1.7Hz,1H),7.94(t,J=1.2Hz,1H),7.89–7.85(m,1H),7.62(dd,J=2.0,1.1Hz,1H),7 .51(dt,J=6.4,3.5Hz,2H),7.45(dd,J=3.6,1.2Hz,1H),7.33(dd,J=5.1,1.2Hz,1H),7.14(dd,J=5.1,3.6Hz,1H),2.74(s,3H); as attached Figure 4 As shown, 13 C NMR (126MHz, CDCl3) δ144.64,135.08,133.85,132.05,131.42,128.69,128.12,126.27,125.85,125.15,124.93,124.10,123.35,122.75,19.47.
[0068] Example 3
[0069] Preparation of 6-chloro-1-methyl-3-phenylnaphthalene
[0070] The molecular formula of the 6-chloro-1-methyl-3-phenylnaphthalene is:
[0071]
[0072] The specific synthesis steps of the 6-chloro-1-methyl-3-phenylnaphthalene include:
[0073]
[0074] In a pressure tube, 2-(2-(phenylethynyl)-6-chloro-phenyl)propan-2-ol (0.2mmol, 1.0equiv.), chloroform (1.5mL) and Tf2O (0.1mmol, 0.5equiv.) were mixed and reacted in an oil bath at 80°C for 3h under air atmosphere. After the reaction, 5mL of water was added to the reaction mixture and extracted with 12mL of ethyl acetate three times, and the organic layer was collected. The organic layer was dried over Na2SO4 and then evaporated under reduced pressure, and then purified by silica gel column chromatography using petroleum ether as eluent to obtain product 2, i.e., 6-chloro-1-methyl-3-phenylnaphthalene, with a yield of 76%.
[0075] The NMR of 6-chloro-1-methyl-3-phenylnaphthalene prepared in this example is shown in the attached Figure 5 and attached Figure 6 As shown in the attached Figure 5 As shown, 1 H NMR (400 MHz, CDCl3) δ8.08–8.00 (m, 1H), 7.97–7.88 (m, 2H), 7.79–7.71 (m, 2H), 7.63 (s, 1H), 7.60–7.44 (m, 4H), 7.44–7.36 (m, 1H), 2.79 (s, 3H); as attached Figure 6 As shown, 13 CNMR (101MHz, CDCl3) δ141.25,138.21,134.87,133.88,131.86,128.87,128.83,127.42,127.29,126.38,126.03,125.83,124.27,124.03,19.58.
[0076] It is understood that the above specific description of the present invention is only used to illustrate the present invention and is not limited to the technical solutions described in the embodiments of the present invention. Those skilled in the art should understand that the present invention can still be modified or replaced by equivalents to achieve the same technical effects; as long as the use requirements are met, they are within the protection scope of the present invention.
Claims
1. A method for synthesizing a naphthalene compound, characterized in that: include: Wherein, X is hydrogen or halogen, and R1 is phenyl or thiophene; The promoter is Tf2O; The solvent is chloroform; The specific steps of the method for synthesizing naphthalene compounds include: In a pressure tube, 0.2 mmol, 1.0 equiv of compound 1, 1.5 mL of solvent and 0.1 mmol, 0.5 equiv of promoter were mixed and reacted in an oil bath under air atmosphere. After the reaction, 5 mL of water was added to the reaction mixture and extracted with 12 mL of ethyl acetate three times, and the organic layer was collected; the organic layer was dried over Na2SO4 and evaporated under reduced pressure, and then purified by silica gel column chromatography using petroleum ether as eluent to obtain product 2.
2. The method for synthesizing naphthalene compounds according to claim 1, wherein: The temperature of the oil bath reaction was 80°C.
3. The method for synthesizing naphthalene compounds according to claim 1, wherein: The oil bath reaction time is 3 h.