Method for catalytically synthesizing 4-fluorotetrahydropyran derivative by using ionic liquid of tetrafluoroboric acid as fluorine source

A fluorotetrahydropyran, ionic liquid technology, applied in the direction of organic chemistry, etc., to achieve the effect of safe and efficient reaction, mild reaction conditions and low toxicity

Active Publication Date: 2018-12-14
SHAANXI NORMAL UNIV +1
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0004] The technical problem to be solved by the present invention is to overcome the defects in the existing 4-fluorotetrahydropyran compound synthesis methods, and to provide a 1-butyl-2,3-dimethylimidazolium tetrafluoroborate As a method for synergistically catalyzing the synthesis of 4-fluorotetrahydropyran compounds as a fluorine source and diacid, the method has mild reaction conditions, less catalyst consumption, short reaction time, and is safe and efficient

Method used

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  • Method for catalytically synthesizing 4-fluorotetrahydropyran derivative by using ionic liquid of tetrafluoroboric acid as fluorine source
  • Method for catalytically synthesizing 4-fluorotetrahydropyran derivative by using ionic liquid of tetrafluoroboric acid as fluorine source
  • Method for catalytically synthesizing 4-fluorotetrahydropyran derivative by using ionic liquid of tetrafluoroboric acid as fluorine source

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0012] Synthesis of 4-fluoro-4-methyl-2-(4-nitrophenyl)-tetrahydropyran with the following structural formula

[0013]

[0014] 0.1511g (1.0mmol) p-nitrobenzaldehyde, 131μL (1.3mmol) 3-methyl-3-buten-1-ol, 0.0248g (0.1mmol) titanocene dichloride, 5-sulfosalicyl Add 0.07626g (0.3mmol) of acid, 0.4800g (2.0mmol) of 1-butyl-2,3-dimethylimidazolium tetrafluoroborate, 3mL of dry dichloromethane into the Shrek tube, and stir the reaction at room temperature After 5 hours, stop the reaction and separate by column chromatography to obtain solid 4-fluoro-4-methyl-2-(4-nitrophenyl)-tetrahydropyran with a yield of 83%, and the structural characterization data are: 1 H NMR (600MHz, CDCl 3 )δ8.15(d, J=8.8Hz, 4H), 7.48(d, J=8.6Hz, 4H), 4.75(d, J=2.1Hz, 1H), 4.73(d, J=2.1Hz, 1H) ,4.07–4.01(m,2H),3.90(td,J=11.6,2.7Hz,2H),2.07(ddt,J=13.7,9.3,2.1Hz,2H),1.83-1.73(m,4H),1.54 (ddd,J=38.3,14.1,11.8Hz,2H),1.41(s,3H),1.38(s,3H); 13 C NMR (151MHz, CDCl 3 )δ149.80(s), 147.29(s), 126.26(s), 123....

Embodiment 2

[0016] Synthesis of 2-(4-chloro-3-nitrophenyl)-4-fluoro-4-methyl-tetrahydropyran with the following structural formula

[0017]

[0018] In this example, the p-nitrobenzaldehyde in Example 1 is replaced with equimolar 4-chloro-3-nitrobenzaldehyde, and the other steps are the same as in Example 1 to obtain solid 2-(4-chloro-3-nitrobenzaldehyde phenyl)-4-fluoro-4-methyltetrahydropyran, its yield is 77%, and the structural characterization data are: 1 H NMR (600MHz, CDCl 3 )δ7.89(d,J=1.7Hz,2H),7.49(dd,J=15.4,5.1Hz,4H),4.71(dd,J=11.7,2.2Hz,2H),4.07-4.02(m,2H ),3.94-3.88(m,2H),2.08(ddt,J=13.8,9.0,2.3Hz,2H),1.85-1.73(m,4H),1.60-1.52(m,2H),1.43(s,3H ),1.40(s,3H); 13 C NMR (151MHz, CDCl 3 )δ148.09(s), 143.25-143.11(m), 131.89(s), 125.87-125.74(m), 73.25(s), 44.00-43.87(m), 36.18(s).

Embodiment 3

[0020] Synthesis of 4-fluoro-4-methyl-2-(4-methoxyphenyl)-tetrahydropyran with the following structural formula

[0021]

[0022] In this example, the p-nitrobenzaldehyde in Example 1 is replaced with equimolar 4-methoxybenzaldehyde, and other steps are the same as in Example 1 to obtain solid 4-fluoro-4-methyl-2-(4 -Methoxyphenyl)-tetrahydropyran, its yield is 68%, and structural characterization data is: 1 H NMR (600MHz, CDCl 3 )δ7.29(d,J=8.6Hz,4H),6.89(d,J=8.7Hz,4H),4.64(dd,J=11.7,1.9Hz,2H),4.05-4.00(m,2H), 3.97-3.90(m,2H),3.80(s,6H),2.05-1.99(m,2H),1.84-1.76(m,4H),1.73-1.65(m,2H),1.44(s,3H), 1.40(s,3H); 13 C NMR (151MHz, CDCl 3 )δ127.27(s), 92.80-92.67(m), 74.72(s), 64.02(s), 43.87(s), 36.61-36.48(m), 27.81(s).

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Abstract

The invention discloses a method for catalytically synthesizing a 4-fluorotetrahydropyran derivative by using an ionic liquid of tetrafluoroboric acid as a fluorine source. According to the method, dichloromethane is used as a solvent, a double acid system of 5-sulfosalicylic acid and titanocene dichloride is used a catalyst, 1-butyl-2,3-dimethylimidazolium tetrafluoroborate is used as the fluorine source, and a Prins cyclization reaction is performed between a homoallylic alcohol compound and aromatic aldehyde under mild conditions to prepare a 4-fluorotetrahydropyran compound. The method provided by the invention is simple in operation steps, mild in conditions, less in catalyst dosage, low in cost, wide in applicability of substrate and high in target compound yield, and can be widely applied to the preparation of 4-fluorotetrahydropyran compounds under acidic reaction conditions.

Description

technical field [0001] The invention belongs to the technical field of synthesis of fluorotetrahydropyran compounds, in particular to a homoallyl alcohol compound with 1-butyl-2,3-dimethylimidazolium tetrafluoroborate as a fluorine source A method for synthesizing 4-fluorotetrahydropyran compounds using a mixture of 5-sulfosalicylic acid and titanocene dichloride as a catalyst under normal temperature conditions with aromatic aldehydes as reaction substrates. Background technique [0002] Tetrahydropyran derivatives are a very important class of oxygen-containing heterocyclic compounds, and their structures widely exist in the structure of natural drug molecules. They are important intermediates for a class of synthetic flavors and fragrances and many natural products, and have a wide range of biological activities. and medicinal value. 4-Fluorotetrahydropyran compounds can simultaneously regulate the electronic effect, lipophilicity and steric effect of the drug because of...

Claims

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Application Information

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IPC IPC(8): C07D309/08C07D409/04C07D407/04
CPCC07D309/08C07D407/04C07D409/04
Inventor 高子伟王芸芸苏洁张伟强简亚军孙华明张国防
Owner SHAANXI NORMAL UNIV
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