CN115108980A - Preparation method of 4-bit acylated derivative of 2-methylquinoline compound - Google Patents
Preparation method of 4-bit acylated derivative of 2-methylquinoline compound Download PDFInfo
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Abstract
The invention belongs to the technical field of chemical synthesis, and particularly relates to a preparation method of a 4-bit acylated derivative of a 2-methylquinoline compound, which is realized by the following steps: mixing the 2-methylquinoline compound with aldehyde, taking Selectfluor as an oxidant, reacting under the catalysis of silver nitrate, and carrying out column chromatography to obtain the 4-bit acylated derivative of the 2-methylquinoline compound. The method provided by the invention is implemented by taking Selectfluor as an oxidant in an aqueous solution under the catalysis of silver nitrate, and has the advantages of good substrate solubility and wide applicability; high reaction yield and strong controllability. The method provided by the invention is green and environment-friendly, has few side reaction products, and is green and efficient.
Description
Technical Field
The invention belongs to the technical field of chemical synthesis, and particularly relates to a preparation method of a 4-bit acylated derivative of a 2-methylquinoline compound.
Background
The 4-bit acylated derivative of the 2-methylquinoline compound belongs to the quinoline compound, and in natural products and medicaments, quinoline and the derivative thereof are ubiquitous and have wide biological activity. Quinoline and derivatives thereof are very important nitrogen-containing heterocyclic compounds and can be widely applied to the fields of medicines, bactericides, herbicides, corrosion inhibitors, functional materials and the like. Quinoline and derivatives thereof are reported to have wide biological activities such as cancer resistance, antibiosis, anti-inflammation, HIV resistance and the like, and in addition, quinoline heterocycles are often introduced into drug molecules as medicine or pesticide parent structures. Therefore, the 4-position acylated derivative for synthesizing the 2-methylquinoline compound has very important pharmaceutical value and economic value.
The Minisci reaction is an effective way to synthesize quinoline derivatives. The Minisci reaction can be carried out at high temperature, but is often accompanied by the formation of a large amount of by-products and the residue of harmful substances. In order to synthesize quinoline derivatives more greenly and efficiently, various catalysts and new technologies are used. Sutherland et al developed a method for the preparation of acyl derivatives at position 4 of 2-methylquinolines by synthesis using triethylchloroformate in combination with TBHP as the acetyl radical source over an iron catalyst. However, the experimental temperature was higher and the productivity was lower (Eur. J. org. chem. 2019, 8, 1815-1819). Wenlong Li et al developed a method for synthesizing quinoline compounds, which can obtain the 4-acylated derivatives of 2-methylquinoline compounds, but the reaction route is complicated and requires more reactants (j. med. chem. 2018, 62, 993-. Therefore, the development of a process with simple synthesis method and good selectivity becomes a problem to be solved urgently.
Disclosure of Invention
Aiming at the problems in the prior art, the invention discloses a preparation method of a 4-bit acylated derivative of a 2-methylquinoline compound, which is simple and convenient to operate, wide in substrate application range, high in yield and strong in applicability.
In order to achieve the purpose, the technical scheme is as follows:
the invention provides a preparation method of a 4-bit acylated derivative of a 2-methylquinoline compound,
the method comprises the following steps:
(1) mixing a 2-methylquinoline compound and aldehyde, taking Selectfluor as an oxidant, and reacting in a solvent under the catalysis of silver nitrate;
(2) obtaining a 4-bit acylated derivative of the 2-methylquinoline compound after column chromatography;
wherein, the structural formula of the 4-bit acylated derivative of the 2-methylquinoline compound is as follows:
in the formula, the R 1 Is halogen, nitro, trifluoromethyl, methyl or hydrogen, R 2 Alkyl and phenyl.
Further, the molar ratio of the 2-methylquinoline compound to the aldehyde is 1: 1.0-5.0; the preferred molar ratio is 1: 3.0.
further, the general formula of the 2-methylquinoline compound is as follows:
and R is halogen, nitro, trifluoromethyl, methyl or hydrogen.
The aldehyde is n-butyraldehyde, isobutyraldehyde or benzaldehyde.
Further, the molar ratio of the 2-methylquinoline compound to the silver nitrate is 1: 0.2-1.0; the preferred molar ratio is 1: 0.25.
further, the molar ratio of the 2-methylquinoline compound to the Selectfluor is 1: 3-6; the preferred molar ratio is 1: 4.
further, the solvent is water; the ratio of the solvent to the silver nitrate solution is 1 mL: 0.025 mmol.
Further, the reaction temperature is 30-50 ℃; the preferred reaction temperature is 30 ℃; the reaction time is 20-24 h.
Further, an eluent for the column chromatography is ethyl acetate and n-hexane according to a volume ratio of 1: 15.
the reaction equation in the invention is as follows:
the invention has the beneficial effects that:
(1) the method provided by the invention is carried out in an aqueous solution under the catalysis of silver nitrate by using the Selectfluor as an oxidant, and has good substrate solubility and wide applicability; high reaction yield and strong controllability.
(2) The method provided by the invention is green and environment-friendly, has few side reaction products, and is green and efficient.
Detailed Description
The following examples further illustrate the technical solutions of the present invention, but should not be construed as limiting the scope of the present invention.
Example 1
2-methylquinoline (1 mmol), n-butyraldehyde (3.0 mmol), silver nitrate (0.25 mmol), Selectfluor (4 mmol) and magnetite were added to an aqueous solution (10 mL) and reacted at 30 ℃ for 24h, 20mL of water and 20mL of ethyl acetate were added, sodium bicarbonate was added and stirred rapidly until no bubbles were produced, ethyl acetate was extracted (3X 20 mL), the organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated. Column chromatography (eluent: ethyl acetate/n-hexane = 1: 15) gave 194.1 mg of 1- (2-methyl-4-quinolyl) -1-butanone, 91% yield.
1 H NMR (400 MHz, CDCl 3 ) δ 8.17 (dd, J = 8.5, 0.8 Hz, 1H), 8.04 (d, J = 8.1 Hz, 1H), 7.70 (ddd, J = 8.4, 6.9, 1.3 Hz, 1H), 7.52 (ddd, J = 8.2, 7.0, 1.2 Hz, 1H), 7.38 (s, 1H), 2.96 (t, J = 7.2 Hz, 2H), 2.77 (s, 3H), 1.79 (h, J= 7.4 Hz, 2H), 1.01 (t, J = 7.4 Hz, 3H). 13 C NMR (101 MHz, CDCl 3 ) δ 204.37 , 158.31 , 148.58 , 144.27 , 129.81 , 129.05 , 127.04 , 124.97 , 122.03 , 119.65 , 44.42 , 25.29 , 17.48 , 13.68 .
Example 2
2-methylquinoline (1 mmol), isobutyraldehyde (3.0 mmol), silver nitrate (0.5 mmol), Selectfluor (4 mmol) and magnetite were added to an aqueous solution (10 mL) and reacted at 30 ℃ for 24h, 20mL water and 20mL ethyl acetate were added, sodium bicarbonate was added and stirred rapidly until no bubbles were produced, ethyl acetate was extracted (3X 20 mL), the organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated. Column chromatography (eluent: ethyl acetate/n-hexane = 1: 15) gave 181.3 mg of 2-methyl-1- (2-methylquinolin-4-yl) propan-1-one, 85% yield.
1 H NMR (400 MHz, CDCl 3 ) δ 8.04 (d, J = 8.4 Hz, 1H), 7.95 (d, J = 8.3 Hz, 1H), 7.73–7.67 (m, 1H), 7.51 (dd, J = 11.3, 3.9 Hz, 1H), 7.32 (s, 1H), 3.37 (dt, J = 13.8, 6.9 Hz, 1H), 2.77 (s, 3H), 1.21 (d, J = 6.9 Hz, 6H). 13 C NMR(151 MHz, CDCl 3 ) δ 208.20 , 158.25 , 148.41 , 145.06 , 129.87 , 129.03 , 126.92 , 124.92 , 122.55 , 118.83 , 40.14 , 25.32 , 18.04 .
Example 3
2-methylquinoline (1 mmol), benzaldehyde (3.0 mmol), silver nitrate (0.25 mmol), Selectfluor (4 mmol) and magnetite were added to an aqueous solution (10 mL) and reacted at 30 ℃ for 24h, 20mL water and 20mL ethyl acetate were added, sodium bicarbonate was added and stirred rapidly until no bubbles were produced, ethyl acetate was extracted (3X 20 mL), the organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated. Column chromatography (eluent: ethyl acetate/n-hexane = 1: 15) gave 162.9 mg of 4-isopropyl-2-methylquinoline, a yield of 88%.
1 H NMR (400 MHz, CDCl 3 ) δ 8.10 (d, J = 8.5 Hz, 1H), 7.86–7.81 (m, 2H), 7.76 (d, J = 8.3 Hz, 1H), 7.73–7.67 (m, 1H), 7.62 (t, J = 7.4 Hz, 1H), 7.45 (dd, J = 15.8, 8.2 Hz, 3H), 7.28 (s, 1H), 2.78 (s, 3H). 13 C NMR (150 MHz, CDCl 3 ) δ 158.71 , 154.16 , 147.98 , 129.38 , 128.69 , 125.22 , 125.04 , 122.79 , 117.63 , 28.09 , 25.41 , 22.80 .
Example 4
6-fluoro-2-methylquinoline (1 mmol), n-butyraldehyde (3.0 mmol), silver nitrate (0.25 mmol), Selectfluor (4 mmol) and magnetite were added to an aqueous solution (10 mL) and reacted at 30 ℃ for 24h, 20mL of water and 20mL of ethyl acetate were added, sodium bicarbonate was added and stirred rapidly until no bubbles were produced, ethyl acetate was extracted (3. x.20 mL), the organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated. Column chromatography (eluent: ethyl acetate/n-hexane = 1: 15) gave 217.4 mg of 1- (6-fluoro-2-methylquinolin-4-yl) butanone, a yield of 94%.
1 H NMR (400 MHz, CDCl 3 ) δ 8.03–8.00 (m, 1H), 7.99 (dd, J = 7.0, 3.8 Hz, 1H), 7.48 (s, 1H), 7.47–7.42 (m, 1H), 2.97 (t, J = 7.2 Hz, 2H), 2.75 (s, 3H), 1.78 (h, J = 7.4 Hz, 2H), 1.00 (t, J = 7.4 Hz, 3H). 13 C NMR(101 MHz, CDCl 3 ) δ 203.42 , 161.05 (d, J = 247.7 Hz), 157.58 (d, J = 2.8 Hz), 145.92 , 142.43 (d, J = 5.8 Hz), 131.33 (d, J = 9.3 Hz), 122.79 (d, J = 10.7 Hz), 121.04 , 119.87 (d, J = 25.8 Hz), 109.09 (d, J = 24.3 Hz), 43.77 , 25.11 , 17.50 , 13.66 .
Example 5
6-chloro-2-methylquinoline (1 mmol), n-butyraldehyde (3.0 mmol), silver nitrate (0.25 mmol), Selectfluor (4 mmol) and magnetite were added to an aqueous solution (10 mL) and reacted at 30 ℃ for 24h, 20mL of water and 20mL of ethyl acetate were added, sodium bicarbonate was added and stirred rapidly until no bubble was generated, ethyl acetate was extracted (3X 20 mL), the organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated. Column chromatography (eluent: ethyl acetate/n-hexane = 1: 15) gave 208.1 mg of 1- (6-chloro-2-methylquinolin-4-yl) butanone, a yield of 84%.
1 H NMR(400 MHz, CDCl 3 ) δ 8.27 (d, J = 2.1 Hz, 1H), 7.93 (d, J = 9.0 Hz, 1H), 7.60 (dd, J = 9.0, 2.2 Hz, 1H), 7.44 (s, 1H), 2.95 (t, J = 7.2 Hz, 2H), 2.74 (s, 3H), 1.77 (h, J = 7.4 Hz, 2H), 1.00 (t, J = 7.4 Hz, 3H). 13 C NMR(151 MHz, CDCl 3 ) δ 203.37 , 158.64 , 147.03 , 142.41 , 133.22 , 130.69 , 130.46 , 124.22 , 122.65 , 120.93 , 43.92 , 25.22 , 17.43 , 13.67.
Example 6
6-bromo-2-methylquinoline (1 mmol), n-butyraldehyde (3.0 mmol), silver nitrate (0.5 mmol), Selectfluor (4 mmol) and magnetite were added to an aqueous solution (10 mL) and reacted at 30 ℃ for 24h, 20mL of water and 20mL of ethyl acetate were added, sodium bicarbonate was added and stirred rapidly until no bubbles were produced, ethyl acetate was extracted (3X 20 mL), the organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated. Column chromatography (eluent: ethyl acetate/n-hexane = 1: 15) gave 245.4 mg of 1- (6-bromo-2-methylquinolin-4-yl) butanone as a product, in 84% yield.
1 H NMR(400 MHz, CDCl 3 ) δ 8.27 (d, J = 2.1 Hz, 1H), 7.93 (d, J = 9.0 Hz, 1H), 7.60 (dd, J = 9.0, 2.2 Hz, 1H), 7.44 (s, 1H), 2.95 (t, J = 7.2 Hz, 2H), 2.74 (s, 3H), 1.77 (h, J = 7.4 Hz, 2H), 1.00 (t, J = 7.4 Hz, 3H). 13 C NMR(151 MHz, CDCl 3 ) δ 203.37 , 158.64 , 147.03 , 142.41 , 133.22 , 130.69 , 130.46 , 124.22 , 122.65 , 120.93 , 43.92 , 25.22 , 17.43 , 13.67.
Example 7
8-fluoro-2-methylquinoline (1 mmol), n-butyraldehyde (3.0 mmol), silver nitrate (0.25 mmol), Selectfluor (4 mmol) and magnetite were added to an aqueous solution (10 mL) and reacted at 30 ℃ for 24h, 20mL of water and 20mL of ethyl acetate were added, sodium bicarbonate was added and stirred rapidly until no bubble was generated, ethyl acetate was extracted (3X 20 mL), the organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated. Column chromatography (eluent: ethyl acetate/n-hexane = 1: 15) gave 212.7 mg of 1- (8-fluoro-2-methylquinolin-4-yl) butanone, a yield of 92%.
1 H NMR(400 MHz, CDCl 3 ) δ 7.95 (d, J = 8.3 Hz, 1H), 7.48–7.36 (m, 3H), 2.97 (t, J = 7.2 Hz, 2H), 2.82 (s, 3H), 1.78 (h, J = 7.4 Hz, 2H), 1.01 (t, J= 7.4 Hz, 3H). 13 C NMR(101 MHz, CDCl 3 ) δ 203.85 , 158.96 (d, J = 1.5 Hz), 157.53 (d, J = 255.9 Hz), 144.03 (d, J = 2.5 Hz), 138.85 (d, J = 11.1 Hz), 126.70 (d, J = 8.1 Hz), 123.69 (d, J = 1.5 Hz), 120.76 (d, J = 4.9 Hz), 120.66 , 113.95 (d, J = 19.0 Hz), 44.34 , 25.48 , 17.43 , 13.65 .
Example 8
2-methyl-6- (trifluoromethyl) quinoline (1 mmol), n-butyraldehyde (3.0 mmol), silver nitrate (0.25 mmol), Selectfluor (4 mmol) and magnetons were added to an aqueous solution (10 mL) and reacted at 30 ℃ for 24h, 20mL of water and 20mL of ethyl acetate were added, sodium bicarbonate was added and stirred rapidly until no bubble was generated, ethyl acetate was extracted (3X 20 mL), the organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated. Column chromatography (eluent: ethyl acetate/n-hexane = 1: 15) gave 244.7 mg of 2, 4-dimethyl-6- (trifluoromethyl) quinoline, a yield of 87%.
1 H NMR (400 MHz, CDCl3) δ 8.60 (s, 1H), 8.11 (d, J = 8.8 Hz, 1H), 7.84 (dd, J = 8.8, 1.6 Hz, 1H), 7.52 (s, 1H), 2.99 (t, J = 7.2 Hz, 2H), 2.79 (s, 3H), 1.84–1.74 (m, 2H), 1.01 (t, J = 7.4 Hz, 3H). 13 C NMR (151 MHz, CDCl3) δ 203.26 , 160.98 , 149.53 , 143.98 , 130.16 , 128.91 (q, J = 32.5 Hz), 126.65 , 125.60 (d, J = 2.9 Hz), 123.95 (d, J = 272.5 Hz), 123.42 (q, J = 4.5 Hz), 121.27 , 44.01 , 25.45 , 17.40 , 13.65 .
Comparative example 1
2-methylquinoline (1 mmol), n-butyraldehyde (3.0 mmol), Selectfluor (4 mmol) and magnetons were added to an aqueous solution (10 mL) and reacted at 30 ℃ for 24h, 20mL of water and 20mL of ethyl acetate were added, sodium bicarbonate was added and stirred rapidly until no bubbles were generated, ethyl acetate was extracted (3X 20 mL), the organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated. Column chromatography (eluent: ethyl acetate/n-hexane = 1: 15) did not yield the desired product 1- (2-methyl-4-quinolinyl) -1-butanone in 0% yield.
Comparative example 2
2-methylquinoline (1 mmol), n-butyraldehyde (3.0 mmol), silver nitrate (0.1 mmol), Selectfluor (4 mmol) and magnetite were added to an aqueous solution (10 mL) and reacted at 30 ℃ for 24h, 20mL of water and 20mL of ethyl acetate were added, sodium bicarbonate was added and stirred rapidly until no bubbles were produced, ethyl acetate was extracted (3X 20 mL), the organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated. Column chromatography (eluent: ethyl acetate/n-hexane = 1: 15) gave 132.2 mg of 1- (2-methyl-4-quinolinyl) -1-butanone, 62% yield.
Comparative example 3
2-methylquinoline (1 mmol), n-butyraldehyde (3.0 mmol), silver nitrate (1.5 mmol), Selectfluor (4 mmol) and magnetite were added to an aqueous solution (10 mL) and reacted at 30 ℃ for 24h, 20mL of water and 20mL of ethyl acetate were added, sodium bicarbonate was added and stirred rapidly until no bubbles were produced, ethyl acetate was extracted (3X 20 mL), the organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated. Column chromatography (eluent: ethyl acetate/n-hexane = 1: 15) gave 177.0 mg of 1- (2-methyl-4-quinolyl) -1-butanone, a yield of 83%.
Comparative example 4
2-methylquinoline (1 mmol), n-butyraldehyde (3.0 mmol), silver nitrate (0.25 mmol), Selectfluor (0.5 mmol) and magnetite were added to an aqueous solution (10 mL) and reacted at 30 ℃ for 24h, 20mL of water and 20mL of ethyl acetate were added, sodium bicarbonate was added and stirred rapidly until no bubble was generated, ethyl acetate was extracted (3X 20 mL), the organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated. Column chromatography (eluent: ethyl acetate/n-hexane = 1: 15) gave 25.6 mg of 1- (2-methyl-4-quinolyl) -1-butanone, 12% yield.
Comparative example 5
2-methylquinoline (1 mmol), n-butyraldehyde (3.0 mmol), silver nitrate (0.25 mmol), Selectfluor (8 mmol) and magnetite were added to an aqueous solution (10 mL) and reacted at 30 ℃ for 24h, 20mL of water and 20mL of ethyl acetate were added, sodium bicarbonate was added and stirred rapidly until no bubbles were produced, ethyl acetate was extracted (3X 20 mL), the organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated. Column chromatography (eluent: ethyl acetate/n-hexane = 1: 15) gave 170.6 mg of 1- (2-methyl-4-quinolyl) -1-butanone, 80% yield.
Comparative example 6
2-methylquinoline (1 mmol), n-butyraldehyde (3.0 mmol), silver nitrate (0.25 mmol), Selectfluor (4 mmol) and magnetite were added to an aqueous solution (10 mL) and reacted at 20 ℃ for 24h, 20mL of water and 20mL of ethyl acetate were added, sodium bicarbonate was added and stirred rapidly until no bubbles were produced, ethyl acetate was extracted (3X 20 mL), the organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated. Column chromatography (eluent: ethyl acetate/n-hexane = 1: 15) gave 142.9 mg of 1- (2-methyl-4-quinolyl) -1-butanone, 67% yield.
Comparative example 7
2-methylquinoline (1 mmol), n-butyraldehyde (3.0 mmol), silver nitrate (0.25 mmol), Selectfluor (4 mmol) and magnetite were added to an aqueous solution (10 mL) and reacted at 60 ℃ for 24h, 20mL of water and 20mL of ethyl acetate were added, sodium bicarbonate was added and stirred rapidly until no bubbles were produced, ethyl acetate was extracted (3X 20 mL), the organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated. Column chromatography (eluent: ethyl acetate/n-hexane = 1: 15) gave 119.4 mg of 1- (2-methyl-4-quinolyl) -1-butanone, 56% yield.
Comparative example 8
2-methylquinoline (1 mmol), n-butyraldehyde (3.0 mmol), copper sulfate (0.25 mmol), Selectfluor (4 mmol) and magnetite were added to an aqueous solution (10 mL) and reacted at 30 ℃ for 24h, 20mL of water and 20mL of ethyl acetate were added, sodium bicarbonate was added and stirred rapidly until no bubbles were produced, ethyl acetate was extracted (3X 20 mL), the organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated. Column chromatography (eluent: ethyl acetate/n-hexane = 1: 15) gave 172.7 mg of 1- (2-methyl-4-quinolinyl) -1-butanone, 65% yield.
Claims (8)
1. A preparation method of a 4-bit acylated derivative of a 2-methylquinoline compound is characterized in that,
the method comprises the following steps:
(1) mixing a 2-methylquinoline compound and aldehyde, taking Selectfluor as an oxidant, and reacting in a solvent under the catalysis of silver nitrate;
(2) obtaining a 4-bit acylated derivative of the 2-methylquinoline compound after column chromatography;
wherein, the structural formula of the 4-bit acylated derivative of the 2-methylquinoline compound is as follows:
in the formula, the R 1 Is halogen, nitro, trifluoromethyl, methyl or hydrogen, R 2 Alkyl and phenyl.
2. The method according to claim 1, wherein the molar ratio of the 2-methylquinoline compound to the aldehyde is 1: 1.0-5.0; the preferred molar ratio is 1: 3.0.
3. the method according to claim 1, wherein the 2-methylquinoline compound has a general formula:
r is halogen, nitro, trifluoromethyl, methyl or hydrogen;
the aldehyde is n-butyraldehyde, isobutyraldehyde or benzaldehyde.
4. The preparation method according to claim 1, wherein the molar ratio of the 2-methylquinoline compound to the silver nitrate is 1: 0.2-1.0; the preferred molar ratio is 1: 0.25.
5. the preparation method according to claim 1, wherein the molar ratio of the 2-methylquinoline compound to the Selectfluor is 1: 3-6; the preferred molar ratio is 1: 4.
6. the method according to claim 1, wherein the solvent is water; the ratio of water to silver nitrate is 1 mL: 0.025 mmol.
7. The method according to any one of claims 1 to 6, wherein the reaction temperature is 30 to 50 ℃; the preferred reaction temperature is 30 ℃.
8. The preparation method according to claim 1, wherein the eluent for the column chromatography is ethyl acetate and n-hexane in a volume ratio of 1: 15.
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